8-Quinolinxanthine and 8-isoquinolinxanthine derivatives as PDE 5 inhibitors

ABSTRACT

A compound of formula (I)  
                 
 
R 1  is hydrogen or alkyl optionally substituted by hydroxy, alkoxy, or alkylthio, R 2  is hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl in which the aryl ring thereof is optionally fused to a 5-membered heterocyclic group or is optionally substituted by one or more substituents selected from alkoxy, amino, alkylamino, dialkylamino, acylamino, halogen, hydroxy, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsufonylamino or dialkylaminosulfonylamino, R 3  is hydrogen or alkyl optionally substituted by hydroxy, alkoxy, or alkylthio, R 4  is hydrogen or alkyl, R 5  is a quinolinyl, isoquinolinyl or oxodihydroisoquinolinyl group optionally fused to a 5-membered heterocyclic group and optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkoxy, alkylthio, alkenyl, alkoxycarbonyl, alkynyl, carboxyl, acyl, a group of formula —N(R 6 )R 7 , aryl optionally substituted by one or more substituents selected from halogen or alkoxy, or heteroaryl having 5 or 6 ring atoms attached through a ring carbon atom to the indicated carbon atom, and R 6  and R 7  are each independently hydrogen or alkyl optionally substituted by hydroxy or alkoxy or one of R 6  and R 7  is hydrogen and the other is acyl, or R 6  and R 7  together with the nitrogen atom to which they are attached denote a 5- or 6- membered heterocyclyl group.

This invention relates to organic compounds, their preparation and theiruse as pharmaceuticals.

In one aspect, the invention provides compounds of formula

-   in free or salt form, where-   R¹ is hydrogen or alkyl optionally substituted by hydroxy, alkoxy,    or alkylthio,-   R² is hydrogen, alkyl, hydroxyalkyl, alkylcarbonyloxyalkyl,    alkoxyalkyl, alkylthioalkyl, alkenyl, cycloalkylalkyl,    heterocyclylalkyl, aralkyl in which the aryl ring thereof is    optionally fused to a 5-membered heterocyclic group or is optionally    substituted by one or more substituents selected from alkoxy, amino,    alkylamino, dialkylamino, acylamino, halogen, hydroxy,    aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,    alkylsufonylamino or dialkylaminosulfonylamino,-   R³ is hydrogen or alkyl optionally substituted by hydroxy, alkoxy,    or alkylthio,-   R⁴ is hydrogen or alkyl,-   R⁵ is a quinolinyl, isoquinolinyl or oxodihydroisoquinolinyl group    optionally fused to a 5-membered heterocyclic group and optionally    substituted by one or more substituents selected from halogen,    cyano, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl,    alkoxy, alkylthio, alkenyl, alkoxycarbonyl, alkynyl, carboxyl, acyl,    a group of formula —N(R⁶)R⁷, aryl optionally substituted by one or    more substituents selected from halogen or alkoxy, or heteroaryl    having 5 or 6 ring atoms, attached through a ring carbon atom to the    indicated carbon atom, and-   R⁶ and R⁷ are each independently hydrogen or alkyl optionally    substituted by hydroxy or alkoxy or one of R⁶ and R⁷ is hydrogen and    the other is acyl, or R⁶ and R⁷ together with the nitrogen atom to    which they are attached denote a 5- or 6- membered heterocyclyl    group.-   “Alkyl” as used herein denotes straight chain or branched alkyl,    which may be, for example, C₁-C₁₀-alkyl such as methyl, ethyl,    n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,    straight or branched pentyl, straight or branched hexyl, straight or    branched heptyl, straight or branched octyl, straight or branched    nonyl or straight or branched decyl. Preferably alkyl is    C₁-C₈-alkyl.

“Alkoxy” as used herein denotes straight chain or branched alkoxy whichmay be, for example, C₁-C₁₀-alkoxy such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight orbranched pentoxy, straight or branched hexyloxy, straight or branchedheptyloxy, straight or branched octyloxy, straight or branched nonyloxyor straight or branched decyloxy. Preferably, alkoxy is C₁-C₄-alkoxy.

“Alkylthio” as used herein may be C₁ to C₁₀-alkylthio such asmethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,sec-butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio,heptylthio, octylthio, nonylthio or decylthio. Preferably alkylthio isC₁ to C₄-alkylthio.

“Alkenyl” as used herein means straight chain or branched alkenyl, whichmay be, for example, C₂ to C₁₀-alkenyl such as vinyl, 1-propenyl,2-propenyl, 1-butenyl, isobutenyl, or straight or branched pentenyl,hexenyl, heptenyl, octenyl, nonenyl or decenyl. Preferred alkenyl is C₂to C₄-alkenyl.

“Cycloalkylalkyl” as used herein denotes alkyl, for example C₁ toC₁₀-alkyl such as one of the C₁ to C₁₀-alkyl groups hereinbeforementioned, substituted by a C₃ to C₈ cycloalkyl group such ascyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methylcyclohexyl, dimethylcyclohexyl, cycloheptyl or cyclooctyl.Preferably, cycloalkylalkyl is C₃-C₆-cycloalkyl-C₁-C₄-alkyl.

“Heterocyclylalkyl” as used herein denotes alkyl, for example C₁ toC₁₀-alkyl such as one of the C₁ to C₁₀-alkyl groups hereinbeforementioned, substituted by a 5- or 6-membered heterocyclyl group havingone or two hetero atoms selected from nitrogen, oxygen and sulfur in thering, such as pyrrolyl, pyrrolidinyl, furyl, thienyl, pyridyl,piperidyl, imidazolyl, imidazolidinyl, pyrazolidinyl, piperazinyl,morpholinyl, oxazolyl, or furazanyl. Preferably, heterocyclylalkyl isC₁-C₄-alkyl substituted by a 5- or 6-membered heterocyclyl group havingone or two nitrogen or oxygen atoms or one nitrogen atom and one oxygenatom in the ring.

“Aralkyl” as used herein means C₆-C₁₀-aryl-C₁-C₁₀ alkyl and may be, forexample, one of the C₁-C₁₀-alkyl groups mentioned hereinbefore,particularly one of the C₁-C₄-alkyl groups, substituted by phenyl,tolyl, xylyl or naphthyl. Preferably, aralkyl is phenyl-C₁-C₄-alkyl,particularly benzyl or 2-phenylethyl.

“Acyl” as used herein denotes alkylcarbonyl, for exampleC₁-C₁₀-alkylcarbonyl where C₁-C₁₀-alkyl may be one of the C₁-C₁₀-alkylgroups hereinbefore mentioned, optionally substituted by one or morehalogen atoms; cycloalkylcarbonyl, for example C₃-C₈-cycloalkylcarbonylwhere C₃-C₈-cycloalkyl may be, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6-memberedheterocyclylcarbonyl having one or two hetero atoms selected fromnitrogen, oxygen and sulfur in the ring, such as furylcarbonyl orpyridylcarbonyl; arylcarbonyl, for example C₆-C₁₀-arylcarbonyl such asbenzoyl; or aralkylcarbonyl, for example C₆ toC₁₀-aryl-C₁-C₄-alkylcarbonyl such as benzylcarbonyl orphenylethylcarbonyl. Preferably acyl is C₁-C₄-alkylcarbonyl.

“Alkynyl” as used herein denotes straight or branched alkynyl, forexample C₂ to C₆-alkynyl such as ethynyl, propargyl, 2-butynyl, pentynylor hexynyl. Preferably alkynyl is C₂-C₄-alkynyl.

“Aryl” as used herein denotes a monovalent carbocylic aromatic group,for example C₆-C₁₀-aryl such as phenyl, phenyl substituted by one ormore, e.g. one, two or three, C₁-C₄-alkyl groups, or naphthyl.Preferably aryl is phenyl.

“Heteroaryl having 5 or 6 ring atoms” as used herein denotes amonovalent aromatic heterocyclic group having 5 or 6 ring atoms of whichone, two or three are selected from nitrogen, oxygen and sulfur, such aspyrrolyl, furyl, thienyl, pyridyl, pyrazolyl, imidazolyl, triazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, dithiazolyl,tritbiazolyl, furazanyl, pyrazinyl, pyrimidinyl or triazinyl.

In alkylamino, dialkylamino, acylamino, dialkylaminosulfonylamino,alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, hydroxyalkyl,alkylthioalkyl and alkoxyalkyl, the alkyl, acyl or alkoxy groups asappropriate have the meanings hereinbefore described.

“Halogen” as used herein may be fluorine, chlorine, bromine or iodine;preferably it is fluorine, chlorine or bromine.

The 5-membered heterocyclic ring to which R⁵ as a quinolinyl,isoquinolinyl or oxodihydroisoquinolinyl group is optionally fused maybe, for example, a 5-membered heterocyclic ring having one or two heteroatoms in the ring, said hetero atoms being selected from oxygen,nitrogen and sulfur. Examples of such heterocyclic rings includepyrrole, pyrroline, pyrrolidine, furan, dihydrofuran, tetrahydrofuran,thiophene, dihydrothiophene, tetrahydrothiophene, imidazole,imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine,dioxolane, oxazole, isoxazole, thiazole and isothiazole rings.Preferably the 5-membered heterocyclic ring is a saturated ring havingtwo hetero atoms, preferably two oxygen or two nitrogen atoms,especially two oxygen atoms.

R⁵ as a quinolinyl group may be a 2-quinolinyl, 3-quinolinyl,4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl or 8-quinolinylgroup, preferably a 4-quinolinyl, 5-quinolinyl or 8-quinolinyl group. R⁵as an isoquinolinyl group may be a 1-isoquinolinyl, 3-isoquinolinyl,4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, or8-isoquinolinyl group, preferably a 1-isoquinolinyl or 4-isoquinolinylgroup. In most of the especially preferred embodiments of the invention,R⁵ is a 4-isoquinolinyl group.

R⁵ as a substituted quinolinyl or isoquinolinyl group is preferablysubstituted by one, two, three or four of the abovementionedsubstituents, especially one, two or three of those substituents. Thepreferred substituted 4-isoquinolinyl group is preferably substituted inthe 1- and/or 6- and/or 7- and/or 8- position of the isoquinoline ringsystem.

In especially preferred embodiments of the invention, R⁵ is a quinolinylgroup of formula

or an isoquinolinyl group of formula

where R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently hydrogen or asubstituent selected from halogen, cyano, hydroxy, alkyl, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, alkoxy, alkylthio, alkenyl, alkoxycarbonyl,alkynyl, carboxyl, acyl, a group of formula —N(R⁶)R⁷, aryl optionallysubstituted by one or more substituents selected from halogen or alkoxy,or heteroaryl having 5 or 6 ring atoms, or R¹¹ and R¹² together with thecarbon atoms to which they are attached denote a 5-membered heterocyclicgroup having two oxygen or nitrogen atoms in the ring, and R⁶ and R⁷ areas hereinbefore defined.

R⁵ as an oxodihydroisoquinolinyl group preferably has the oxo grouportho to the ring nitrogen atom, preferably in the 1-position in theisoquinoline ring system. It is preferably linked to the remainder ofthe molecule of formula I via the ring carbon atom meta to the ringnitrogen atom, i.e. the 4-position in the isoquinoline ring system. Anespecially preferred oxodihydroisoquinolinyl group is of formula

where R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore defined and R^(a) ishydrogen or C₁-C₄-alkyl.

Preferred among the compounds of formula I in free or salt form arethose where

-   R¹ is hydrogen or C₁-C₄-alkyl optionally substituted by hydroxy,    C₁-C₄-alkoxy or C₁-C₄-alkylthio,-   R² is hydrogen, C₁-C₈-alkyl, hydroxy-C₁-C₈-alkyl,    C₁-C₄-alkylcarbonyloxy —C₁-C₈alkyl, C₁-C₄-alkoxy —C₁-C₈-alkyl,    C₁-C₄-alkylthio-C₁-C₈-alkyl, C₂-C₄-alkenyl,    C₃-C₈-cyloalkyl-C₁-C₄-alkyl, heterocyclyl-C₁-C₄-alkyl where the    heterocyclyl group is a 5- or 6-membered heterocyclyl group having    one or two hetero atoms selected from nitrogen and oxygen atoms in    the ring, phenyl-C₁-C₄-alkyl in which the phenyl ring is optionally    substituted by one or more substituents selected from C₁-C₄-alkoxy,    amino, C₁-C₄-alkylamino, di(C₁-C₄-alkyl)amino,    C₁-C₄-alkylcarbonylamino, halogen, C₁-C₄-alkylsulfonylamino, or    di(C₁-C₄-alkyl)aminosulfonylamino, and is optionally fused to a    5-membered heterocyclic ring having two oxygen or two nitrogen atoms    in the ring,-   R³ is hydrogen or C₁-C₄-alkyl optionally substituted by hydroxy,    C₁-C₄-alkoxy or C₁-C₄-alkylthio,-   R⁴ is hydrogen or C₁-C₄-alkyl,-   R⁵ is a quinolinyl, isoquinolinyl or oxodihydroisoquinolinyl group    optionally fused to a 5-membered heterocyclic group having two    oxygen or two nitrogen atoms in the ring and optionally substituted    by one or more substituents selected from halogen, cyano, carboxy    hydroxy, C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,    C₁-C₄-alkylthio-C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio,    C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-alkylcarbonyl, a group —N(R⁶)R⁷    or phenyl optionally substituted by one or more substituents    selected from halogen or C₁-C₄-alkoxy and-   R⁶ and R⁷ are each independently hydrogen or C₁-C₄-alkyl optionally    substituted by hydroxy or alkoxy, or one of R⁶ and R⁷ is hydrogen    and the other is C₁-C₄-alkylcarbonyl, or R⁶ and R⁷ together with the    nitrogen atom to which they are attached denote a 5- or 6-membered    heterocyclyl group having one or two nitrogen atoms and, optionally,    an oxygen atom in the ring.

Further preferred among the compounds of formula I are those where

-   R¹ is hydrogen or C₁-C₄-alkyl, R² is hydrogen, C₁-C₈-alkyl, hydroxy    -C₁-C₈-alkyl, or C₁-C₄-alkylcarbonyloxy-C₁-C₈-alkyl, C₂-C₄-alkenyl,    C₃-C₆-cycloalkyl-C₁-C₄-alkyl, heterocyclyl-C₁-C₄-alkyl where the    heterocyclyl group is a 5-membered heterocyclyl group having one    nitrogen or oxygen atom in the ring, phenyl-C₁-C₄-alkyl in which the    phenyl ring is optionally substituted by one or two substituents    selected from C₁-C₄-alkoxy, amino, C₁-C₄-alkylcarbonylamino,    chlorine, bromine, C₁-C₄-alkylsulfonylamino, or    di(C₁-C₄-alkyl)aminosulfonylamino and is optionally fused to a    5-membered heterocyclic ring having two oxygen atoms in the ring,-   R³ is hydrogen or C₁-C₄-alkyl,-   R⁴ is hydrogen or C₁-C₄-alkyl,-   R⁵ is a quinolinyl group of formula II, an isoquinolinyl group of    formula III or an oxodihydroisoquinolinyl group of formula IIIA,    where R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently selected    from hydrogen, halogen, cyano, carboxy, hydroxy, C₁-C₄-alkyl,    hydroxy-C₁-C₄ -alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,    C₁-C₄-alkylthioC₁-C₄-alkyl, C₁-C₄-alkoxy, C_(l)-C₄-alkylthio,    C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-alkylcarbonyl, a group —N(R⁶)R⁷    or phenyl optionally substituted by one or two substituents selected    from halogen or C₁-C₄-alkoxy, or R¹¹ and R¹² together with the    carbon atoms to which they are attached denote a 5-membered    heterocyclic group having two oxygen atoms in the ring, and-   R⁶ and R⁷ are each independently hydrogen or C₁-C₄-alkyl optionally    substituted by hydroxy or alkoxy or one of R⁶ and R⁷ is hydrogen and    the other is C₁-C₄-alkylcarbonyl, or R⁶ and R⁷ together with the    nitrogen atom to which they are attached denote a 6-membered    heterocyclyl group having one or two nitrogen atoms, or one nitrogen    atom and one oxygen atom, in the ring.

Amongst the further preferred compounds hereinbefore described,especially preferred compounds are usually those in which R⁵ is anisoquinolinyl group of formula III in which R⁸ is hydrogen, C₁-C₄-alkyl,halogen, cyano, —N(R⁶)R⁷ where R⁶ and R⁷ are independently C₁-C₄-alkylor R⁶ and R⁷ together with the nitrogen atom to which they are attacheddenote a 6-membered heterocyclyl group having one or two nitrogen atoms,or one nitrogen atom and one oxygen atom, in the ring, or phenylsubstituted by one or two C₁-C₄-alkoxy groups; R⁹ and R¹⁰ are eachindependently hydrogen, C₁-C₄-alkyl or halogen; R¹¹ and R¹² are eachindependently hydrogen, halogen, cyano, carboxy, hydroxy, C₁-C₄-alkyl,C₁-C₄-alkoxy or C₂-C₄-alkynyl, or R¹¹ and R¹² together with the carbonatoms to which they are attached denote a 5-membered heterocycle havingtwo oxygen atoms in the ring; and R¹³ is hydrogen or halogen.

Specific especially preferred compounds of formula I are thosehereinafter described in the Examples. More preferred amongst thesecompounds are those of Examples 7, 10, 15, 35, 45, 49, 55, 60, 68 and70.

Compounds of formula I may be in the form of salts, particularlypharmaceutically acceptable salts. Pharmaceutically acceptable acidaddition salts of compounds of formula I include those of inorganicacids, for example, hydrohalic acids such as hydrofluoric acid,hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid,sulfuric acid, phosphoric acid; and organic acids, for, examplealiphatic monocarboxylic acids such as formic acid, acetic acid,trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxyacids such as lactic acid, citric acid, tartaric acid or malic acid,dicarboxylic acids such as maleic acid or succinic acid, aromaticcarboxylic acids such as benzoic acid, p-chlorobenzoic acid,diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids suchas o-hydroxybenzoic acid, p-hydroxybenzoic acid,1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid. Pharmaceuticallyacceptable base salts of compounds of formula I where R³ is hydrogeninclude metal salts, particularly alkali metal or alkaline earth metalsalts such as sodium, potassium, magnesium or calcium salts, and saltswith ammonia or pharmaceutically acceptable organic amines orheterocylic bases such as ethanolamines, benzylamines or pyridine. Thesesalts may be prepared from free compounds of formula I or other salts ofcompounds of formula I by known salt-forming procedures.

The present invention also provides a process for the preparation ofcompounds of formula I in free or salt form which comprises1) (a) dehydrating a compound of formula

-   where R¹, R², R⁴ and R⁵ are as hereinbefore defined; or-   (b) for the preparation of a compound of formula I in free or salt    form where R³ is alkyl optionally substituted by hydroxy, alkoxy or    alkylthio, reacting a compound of formula I in: free or salt form    with an appropriate alkylating agent, or-   (c) for the preparation of a compound of formula I in free or salt    form where R² is aralkyl substituted in the aryl ring by    alkylsulfonylamino or dialkylaminosulfonylamino, reacting a compound    of formula I in salt form where R² is aralkyl substituted by amino    with, respectively, an alkylsulfonyl halide or dialkylaminosulfonyl    halide; or-   (d) for the preparation of a compound of formula I in free or salt    form where R² is hydroxy-substituted alkyl, hydration of a compound    of formula I where R² is alkenyl; or-   (e) for the preparation Of a compound of formula I in free or salt    form where R² is alkyl substituted by alkylcarbonyloxy, appropriate    esterification of a compound of formula I where R² is    hydroxy-substituted alkyl; or-   (f) for the preparation of a compound of formula I in free or salt    form where R² is aralkyl substituted in the aryl ring by amino,    hydrolysing a compound of formula I where R² is aralkyl substituted    in the aryl ring by acylamino; or-   (g) for the preparation of a compound of formula I in free or salt    form where R⁵ is quinolinyl or isoquinolinyl substituted by hydroxy,    dealkylation of a compound of formula I where R⁵ is respectively    quinolinyl or isoquinolinyl substituted by alkoxy, particularly    methoxy; or-   (h) for the preparation of a compound of formula I in free or salt    form where R⁵ is quinolinyl or isoquinolinyl substituted by halogen,    halogenation of a compound of formula I where R⁵ is respectively    quinolinyl or isoquinolinyl having an unsubstituted ring carbon atom    available for halogenation; or-   (i) for the preparation of a compound of formula I in free or salt    form where R² is a cyclopropyl group, optionally substituted by    alkyl, subjecting a compound of formula I where R² is alkenyl to a    Simmons Smith cyclopropanation reaction; and    2) recovering the resulting product of formula I in free or salt    form.

Process (a) may be carried out by heating, or by reaction with aninorganic or organic base. It may be effected in an organic or aqueoussolvent or mixed aqueous/organic solvent. The reaction with base may becarried out at ambient temperature or, more conveniently, at elevatedtemperature. The reaction is preferably carried out by treatment withaqueous alkali metal hydroxide in an alcoholic solvent at elevatedtemperature, for example as described hereinafter in the Examples. Thecompound of formula IV is preferably a compound where R⁵ is a group offormula I or III. Compounds of formula IV may be prepared by reacting acompound of formula

where R¹ and R² are as hereinbefore defined, with a compound of formula

or an amide-forming derivative thereof, where R⁴ and R⁵ are ashereinbefore defined. The reaction may be effected by treating thecarboxylic acid of formula VI with a peptide coupling agent to form insitu an activated ester or mixed anhydride, followed by treatment withthe compound of formula V in an organic, e.g. dipolar aprotic, or mixedaqueous-organic (e.g. chlorohydrocarbon) solvent. The latter treatmentmay be carried out at sub-ambient, ambient or elevated temperature,conveniently at ambient temperature. Preferably, the acid of formula VIis treated with a carbodiimide derivative in the presence ofhydroxybenzotriazole and, optionally, a base, or is treated with abenzotriazolyl-(trisdialkylamino)-oxyphosphonium salt. The resultingintermediate is preferably treated with the compound of formula V in adipolar aprotic solvent or mixed chlorohydrocarbon-aqueous solvent atambient temperature. Procedures may be as hereinafter described in theExamples.

Compounds of formula V may be prepared by reduction of a compound offormula

where R¹ and R² are as hereinbefore defined.

The reduction may be effected using known procedures, for example bytreating the compound of formula VII with a reducing agent in an organicor aqueous solvent. The reaction may be carried out at ambient or, moreconveniently, at elevated temperature. Preferred reducing agents arealkali metal dithionite salts in aqueous media or hydrogen in thepresence of a noble metal catalyst. Treatment with sodium dithionite inaqueous solution at 80-90° C. is particularly preferred.

Compounds of formula VII may be prepared by nitrosation of a compound offormula

where R¹ and R² are as hereinbefore defined, for example with an organicor inorganic nitrosating agent in an organic or aqueous or mixedorganic-aqueous solvent. Nitrosation may be effected using knownprocedures at sub-ambient, ambient or elevated temperature, preferablywith an alkali metal nitrite such as sodium nitrite in the presence ofan acid such acetic acid at sub-ambient or ambient temperature,preferably in a mixed alcoholic-aqueous solvent such as aqueous ethanol.

Compounds of formula VIII may be prepared by reacting a compound offormula

where R² is as hereinbefore defined with an inorganic or organic base toeffect cyclisation, followed, where R¹ is an optionally substitutedalkyl group, by reaction with an alkylating agent. The cyclisationreaction may be effected using conventional procedures. It isconveniently carried out in an aqueous, organic or mixed organic-aqueoussolvent. Reaction may be effected at ambient or, more conveniently,elevated temperature. The base is preferably an alkali metal hydroxide,especially sodium hydroxide, which is preferably reacted in a mixedaqueous-alcoholic solvent, preferably at elevated temperature, e.g.80-90° C. The optional alkylation step can be effected using knownprocedures, for example in the presence of an inorganic or organic base,for example in an aqueous, organic or mixed aqueous-organic solvent.Alkylation may be carried out at sub-ambient temperature or, moreconveniently, at ambient or elevated temperature. Preferred alkylatingagents are alkyl iodides or, especially, dialkyl sulfates. Preferredbases are alkali metal hydroxides in aqueous alcoholic solvents,especially aqueous ethanol.

Compounds of formula IX may be prepared by reacting a compound offormula

with cyanoacetic acid or an amide-forming derivative thereof such as anester or acid halide thereof, preferably the acid or its ethyl ester.The reaction may be effected using known procedures, for example in anorganic solvent, preferably an anhydride such as acetic anhydride. Thereaction temperature may be ambient or, more conveniently, elevatedtemperature, e.g. 65 to 70° C.

Compounds of formula X may be prepared using conventional procedures,for example from an isocyanate R²NCO by reaction with gaseous or aqueousammonia or from an amine R²NH₂ by reaction with a metal cyanate, forexample as hereinafter described in the Examples.

Compounds of formula VIII where R¹ is alkyl optionally substituted byhydroxy, alkoxy or alkylthio and R² is as hereinbefore defined otherthan hydrogen, may be prepared by hydrogenolysis of a compound offormula

where R¹ is alkyl optionally substituted by hydroxy, alkoxy oralkylthio, R² is as hereinbefore defined other than hydrogen and Ar isphenyl optionally substituted by one or more C₁-C₄-alkoxy, preferablymethoxy, groups. The hydrogenolysis may be carried out in a knownmanner, e.g. by treatment with hydrogen or a source of hydrogen and ametal catalyst such as a platinum or, preferably, palladium catalyst.The reaction may be carried out in an organic solvent. The reactiontemperature may be ambient or elevated. Preferably hydrogenolysis iseffected using palladium black in formic acid, e.g. as hereinafterdescribed in the Examples.

Compounds of formula XI may be prepared by reacting a compound offormula

where R¹ and R² are as hereinbefore defined for formula XI, with acompound of formula ArCH₂NH₂ where Ar is as hereinbefore defined. Thereaction may be carried out in a known manner, e.g. in an organicsolvent, preferably an alcohol such as n-butanol, at ambient or elevatedtemperature, or analogously as hereinafter described in the Examples.

Compounds of formula XII may be prepared by reacting a compound offormula

where R¹ is as hereinbefore defined for formula XI, with a compound offormula R²X where R² is as hereinbefore defined for formula XI and X ishalogen or hydroxy, where X is hydroxy, the reaction being carried outin the presence of activating reagents, preferably an azodicarboxylatesuch as di-t-butyl azodicarboxylate together with a triarylphosphinesuch as diphenylpyridylphosphine. The reaction may be carried out in anorganic solvent, preferably an ether such as dioxan. The reactiontemperature may be sub-ambient or, preferably, ambient or elevatedtemperature. The reaction may be carried out using the procedure ofMitsonobu, Synthesis 1981, 1, or analogously as hereinafter described inthe Examples. Compounds of formula XIII are known or may be prepared byknown procedures.

Compounds of formula VI may be prepared, for example, (i) frombenzaldehyde or a substituted benzadehyde using the procedure of Dyke etal, Tetrahedron 1968, 24, 1467 or (ii) from an optionally substituted,N-protected 1,2-dihydroisoquinoline by reaction with a 2-oxo carboxylicacid using the procedure of Dyke. et al, Tetrahedron 1968, 24, 1467,optionally followed by conversion of the resulting carboxylic acid intoa methyl ester and then an alkali metal salt using the procedure of J.March, Advanced Organic Chemistry, 4th Edition, Wiley, N.Y., 1992, pages393 and 378 or (iii) from an optionally substituted quinoline orisoquinoline by reaction with a hydride reducing agent followed by a2-oxo-carboxylic ester using the procedure of Minter et al, J. Org.Chem. 1988, 53, 2653 or (iv) by introducing substituents onto theN-containing ring of an acid of formula VI using the procedures of Janinand Biagani, Tetrahedron 1993, 39, 10305, or Ford et al, J. Med. Chem,1985, 28, 164.

Certain preferred compounds of formula VI may be prepared by

-   (i) the reaction sequence    where R⁴, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore defined.    Steps (a) to (c) may be carried out in a known manner, e.g. using    the procedure of Dyke et al, Tetrahedron 1968, 24, 1467, or    analogously as hereinafter described in the Examples;-   (ii) the reaction sequence    where R¹, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore defined.    Steps (d) to (g) may be carried out in a known manner, e.g. step (d)    using the procedure of Katayama et al, Chem. Pharm. Bull, 1980, 28,    2226, step (e) using the procedure of Dyke et al. Tetrahedron 1968,    24, 1467 and steps (f) and (g) using the procedure of J. March,    Advanced Organic Chemistry, 4th Edition, Wiley, N.Y., 1992, pages    393 and 378, or analogously as hereinafter described in the    Examples;-   (iii) the reaction    e.g. by treatment of XVIII with a hydride reducing agent, followed    by a 2oxo-carboxylic ester, using the procedure of Minter et al, J.    Org. Chem. 1988, 53, 2653, or analogously as described hereinafter    in the Examples;-   (iv) for the preparation of compounds of formula VI in which R⁵ is a    4-isoquinolinyl group substituted in the 1- position, the reaction    sequence    where R⁴, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore    defined. Steps (h) to (k) may be carried out in a known manner, e.g.    steps (h) to (j) using the procedure of Janin and Biagni,    Tetrahedron, 1993, 39, 10305 and step (k) using the procedure of J.    March, Advanced Organic Chemistry, 4th Edition, New York, 1992, page    378 or analogously as hereinafter described in the Examples;-   (v) for the preparation of compounds of formula VI in which R⁵ is an    isoquinolinyl group of formula III in which R⁸ is cyano, the    reaction sequence    where R⁴, R^(9,) R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore defined.    Steps (l) to (n) may be carried out in a known manner, e.g.    steps (l) and (m) using the procedure of Ford et al, J.. Med. Chem.,    1985, 28, 164 and step (n) using the procedure of J. March, op.    cit., page 378;-   (vi) for the preparation of compounds of formula VI in which R⁵ is    an oxodihydroisoquinolinyl group, the reaction sequence    where R⁴, R^(9,) R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore defined.    Steps (o) and (p) may be carried out in a known manner, e.g. using    the procedure of Holzgrabe, Arch. Pharm. (Weinheim, Ger.), 1988,    321, 767, or analogously as hereinafter described in the Examples;-   (vii) for preparation of compounds of formula VI where R⁵is a    quinolinyl group, the reaction    where R⁴, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore defined,    which may be carried out in a known manner, e.g. by treatment with a    strong base, preferably an alkali metal dialkylamide such as lithium    diisopropylamide, followed by treatment with carbon dioxide, e.g.    using the procedure of using Brown and Curless, Tetrahedron Lett.,    1986, 27, 6005, or analogously as hereinafter described in the    Examples.-   (viii) for the preparation of compounds of formula VI where R⁵ is a    4-isoquinolinyl group,    where R⁸, R¹⁰, R¹¹, R¹² and R¹³ are as hereinbefore defined.    Steps (q) to (w) may be carried out in a known manner; e.g. step (q)    by treatment with a carboxyethyltriarylphosphonium ylid, preferably    carboxyethyltriphenylphosphonium ylid in an organic solvent,    preferably an ether or hydrocarbon, especially toluene, at    sub-ambient, elevated or, preferably, ambient temperature; step (r)    by treatment with nitromethane in the presence of an inorganic or,    preferably, amine base, especially tetramethylguanidine, for example    in the presence of a solvent or, preferably, in the absence of a    solvent, at sub-ambient, ambient or, preferably, elevated    temperature, e.g. 60-80° C.; step (s) by treatment with a reducing    agent, preferably a tin (II) salt, especially tin (II) chloride    hydrate, in an aqueous or, preferably, organic solvent, preferably    an alcohol such as ethanol, at sub-ambient, ambient or, preferably,    elevated temperature, e.g. wider reflux; step (t) by treatment with    an acid halide or anhydride, preferably the acid chloride, of the    acid R⁸COOH, at elevated or, preferably, sub-ambient or ambient    temperature, eg. 0° C. to ambient temperature, in an aqueous or,    preferably, organic solvent, especially a chlorinated solvent such    as dichloromethane, preferably in the presence of a base, especially    an amine such as triethylamine; step (u) by treatment with a    phosphorus (V) halide or oxyhalide, preferably phosphorous    pentachloride or phosphorus oxychloride, preferably in an organic    solvent such as a hydrocarbon or nitrile, especially acetonitrile,    preferably at ambient or, especially, elevated temperature, e.g.    under reflux; step (v) by treatment with a noble metal, preferably    palladium, catalyst, preferably in an organic solvent, especially a    hydrocarbon such as decalin, preferably at elevated temperature,    e.g. under reflux; step (w) by treatment with an alkali metal    hydroxide, preferably lithium or sodium hydroxide, in organic,    aqueous or mixed organic-aqueous solvent, preferably THF-water, at    sub-ambient, elevated or, preferably, ambient temperature; specific    methods for steps (q) to (w) being as hereinafter described in the    Examples.-   (ix) the reaction sequence    where R⁹, R¹¹, R¹² and R¹³ are as hereinbefore defined, Ac is an    acyl group, and Y is halogen. Steps (x) to (za) may be effected in a    known manner, e.g. step (x) by reaction with a halogenation agent,    e.g. bromine or a N-halosuccinimide, preferably N-chlorosuccinimide,    e.g. as described in J. March, op. cit., page 531; step (y) by    reaction with a reducing agent, e.g. a metal hydride, in the    presence of an acylating agent, e.g. acetic anhydride, e.g. as    described in Katayama et al, op. cit; step (z) by reaction with a    2-oxocarboxylic acid, preferably glyoxylic acid, in the presence of    a mineral acid, e.g. as described in Dyke et at, Tetrahedron 1968,    24, 1467; and step (za) by treatment with a reducing agent, e.g. as    described in J. March et al, op. cit, page 566; or analogously as    described hereinafter in the Examples.

Certain compounds of formula V are novel, including Intermediates 1 to10 as described hereinafter. Certain compounds of formula VI are novel,including Intermediates 20 to 48 as described hereinafter.

Process variant (b) may be carried out in a known manner, for example byreacting a compound of formula I where R³ is hydrogen with anappropriate alkylating agent, preferably an alkyl iodide or dialkylsulfate, such as a compound of formula R³I or (R³)₂SO₄ where R³ isC₁-C₄-alkyl. The reaction may be conducted in the presence of aninorganic or organic base, for example in an aqueous, organic or mixedaqueous-organic solvent. Alkylation may be carried out at sub-ambienttemperature or, more conveniently, at ambient or elevated temperature.Preferred bases are alkali metal carbonates. Preferred solvents areorganic dipolar aprotic solvents, especially N,N-dimethylformamide.

Process variant (c) may be effected using known sulfonylationprocedures, e.g. in the presence of an organic or inorganic base,preferably a tertiary organic base such as pyridine. The reactiontemperature may be sub-ambient, ambient or, preferably, elevated.Preferred procedures are as hereinafter described in the Examples.

Process variant (d) may be effected using known procedures, e.g. bytreating a compound of formula I wherein R² is alkenyl with ahydroborating agent, followed by oxidative basic work-up. Hydroborationmay be carried out at sub-ambient or, more conveniently, at ambient orelevated, temperature. Preferred hydroborating agents are dialkylboranessuch as 9-borabicyclo[2.2.0]nonane, which are preferably reacted underreflux. Oxidative work-up is preferably conducted with hydrogen peroxideand an alkali metal hydroxide, preferably sodium hydroxide. The work-uptemperature is preferably 40-60° C.

Process variant (e) may be carried out using conventional esterificationprocedures, e.g. by reacting the compound of formula I wherein R² ishydroxy with a carboxylic acid or halide thereof, preferably an acidchloride, in the presence of an organic or inorganic base, atsub-ambient or, preferably, ambient or elevated (e.g. 40-60° C.)temperature. Preferred bases are organic tertiary bases such aspyridine.

Process variant (f) may be carried out using known procedures forconversion of acylamino into amino, e.g.. by treatment with a mineralacid such as sulphuric or, preferably, hydrochloric acid. The reactionis preferably carried out in a mixed aqueous-organic solvent such asaqueous ethanol. The reaction temperature is conveniently ambient or,preferably, elevated temperature, especially reflux temperature.

Process variant (g) may be effected using known dealkylation methods,e.g. by reaction with HBr or HI, usually at elevated temperature,preferably by heating with concentrated hydrobromic acid, e.g. ashereinafter described in the Examples.

Process variant (h) may be effected using known halogenation procedures,e.g. by reaction with bromine or chlorine in a solvent such as aceticacid. The reaction is conveniently carried at ambient temperature, e.g.as hereinafter described in the Examples.

Process variant (i) may be effected using known procedures for theSimmons Smith reaction, e.g. by reaction with diethyl zinc andchloroiodomethane. The reaction is usually carried out in an organicsolvent, preferably a halohydrocarbon. The reaction is suitably carriedout at ambient temperature, e.g. as hereinafter described in theExamples.

Compounds of formula I in free form may be converted into salt form, andvice versa, in a conventional manner. The compounds in free or salt formcan be obtained in the form of hydrates or solvates containing a solventused for crystallization. The compounds of formula I in free or saltform can be recovered from reaction mixtures in a conventional manner.Isomer mixtures can be separated into individual isomers, e.g.enantiomers, in a conventional manner, e.g. by fractionalcrystallization.

Compounds of formula I in free or pharmaceutically acceptable salt form,hereinafter referred to alternatively as agents of the invention, areuseful as pharmaceuticals. In particular, they are inhibitors of cyclicguanosine-3′,5′-monophosphate phosphodiesterases (cGMP PDEs), especiallyPDE5. Agents of the invention are selective PDE5 inhibitors; inparticular, they exhibit good selectivity for inhibition of PDE5relative to inhibition of other phosphodiesterases, particularly PDE1and PDE6, indicating a low side-effect profile.

Furthermore agents of the invention have an appropriate duration ofaction and many have a rapid onset of action. The inhibiting propertiesof agents of the invention may be demonstrated in the following testprocedure:

PDE5 Assay: A 10 mM solution of a test compound in DMSO is diluted100-fold with aqueous 20% v/v DMSO to give a 100 μM stock solution,which is further diluted with aqueous 20% v/v DMSO to give ten solutionshaving concentrations from 10 μM to 0.00051 μM. 10 μL of each of thesesolutions is transferred to a selected well of a 96-well Optiplatemicrotitre plate (ex Packard). To determine total binding, 10 μl ofaqueous 20% v/v DMSO is added to other selected wells. To determinenon-specific binding, a 10 mM solution of sildenafil in 100% DMSO isdiluted 20-fold with aqueous 20% v/v DMSO and 10 μl of the resultingsolution is added to further selected wells of the Optiplate plate. Toall wells containing test compound solution, aqueous DMSO or sildenafilsolution is added 80 μl of Assay Mix, prepared by mixing PDE AssayBuffer (2 ml), an aqueous solution of bovine serum albumin (BSA)containing 5 mg BSA/ml (2 ml), an aqueous 75 μM solution of cGMP sodiumsalt (0.2 ml), 3H-cGMP (ex Amersham, 10 μl) and distilled water (11.8ml). (The PDE Assay Buffer is prepared by dissolving Tris-base (7.56 g)in water (800 ml), adding 1M aqueous MgCl₂ (10.325 ml) and 0.5 M EDTA(4.25 ml), adjusting the pH to 7.5 with 1N hydrochloric acid and makingup to 1 litre with water). A solution of human PDE5, partially purifiedfrom human platelets (11 μl, containing 0.017 units of PDE5 per ml,where 1 unit hydrolyses 1.0 μmole of 3′,5′-cyclic GMP to 5′-GMP perminute at pH 7.5 at 37° C.), in 20 mM Hepes, pH7.4, 100 mM sodiumchloride, 10% v/v glycerol, 1 mM benzamidine and 2 mM dithiotherietol,is diluted 200-fold, with Enzyme Buffer prepared by adding 0.5M EDTA (2ml) to a solution of Tris-Base (1.21 g) in water (800 ml), adjusting thepH to 7.5 with 1N HCl and making up to 1litre with water. The dilutedPDE5 solution (10 μl) is added to all wells containing test compound,aqueous DMSO or sildenafil solution. The plate is incubated at roomtemperature for 1 hour. 50 μl of a suspension of 500 mg PDE Yttriumsilicate SPA beads (ex Amersham) in 28 ml water is added to each of thewells and the plate is incubated for a further 20 minutes and thensealed using Top Seal-S (ex Packard) according to the manufacturer'sinstructions. The resulting scintillations are counted using a CanberraPackard Top Count (1 minute per well), as a measure of the extent towhich binding of PDE5 to the beads is inhibited. The concentration oftest compound at which 50% inhibition of PDE5 binding to the beadsoccurs (IC₅₀) is determined from concentration-inhibition curves in aconventional manner.

Compounds of the Examples hereinbelow have IC₅₀ values of the order offrom 0.005 μM to 10 μM in the above assay. For example, the compounds ofExamples 7, 10, 15, 35, 45, 49, 55, 60, 68 and 70 have IC₅₀ values of0.007 μM, 0.01 μM, 0.006 μM, 0.010 μM, 0.002 μM, 0.0037 μM, 0.0055 μM,0.0028 μM, 0.007 μM and 0.009 μM respectively in the above assay.

Having regard to their inhibition of PDE5, agents of the invention areuseful in the treatment of conditions which are mediated by PDE5.Treatment in accordance with the invention may be symptomatic orprophylactic.

Accordingly, agents of the invention are useful in the treatment ofsexual dysfunction, including male erectile dysfunction and femalesexual dysfunction, premature labour, dysmenorrhoea, benign prostatichyperplasia, bladder outlet obstruction, incontinence, stable, unstableand variant (Prinzmetal) angina, hypertension, pulmonary hypertension,congestive heart failure, atherosclerosis, conditions of reduced bloodvessel patency, e.g. post-percutaneous transluminal coronaryangioplasty, peripheral vascular disease, bronchitis, asthma, allergicrhinitis, glaucoma, tinnitus, diseases characterised by disorders of gutmotility, e.g. irritable bowel syndrome, pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, peripheral diabeticneuropathy, stroke, Alzheimer's disease, acute respiratory failure,psoriasis, skin necrosis, cancer, metastasis, baldness, nutcrackeroesophagus, anal fissure and hypoxic vasoconstriction.

Agents of the invention are of particular interest for use in thetreatment of sexual dysfunction, especially male erectile dysfunction.

In accordance with the foregoing, the invention also provides a methodfor the treatment of a condition mediated by PDE5, for example acondition mentioned hereinbefore, particularly sexual dysfunction,especially male erectile dysfunction, which comprises administering to asubject, particularly a human subject, in need thereof an effectiveamount of a compound of formula I in free form or in the form of apharmaceutically acceptable salt. In another aspect, the inventionprovides a compound of formula I, in free form or in the form of apharmaceutically acceptable salt, for use in the manufacture of, amedicament for the treatment of a condition mediated by PDE5, forexample a condition as mentioned hereinbefore, particularly sexualdysfunction, especially male erectile dysfunction.

Agents of the invention may be administered by any appropriate route,e.g. orally, for example in the form of a tablet, a capsule, a solutionor a suspension; parenterally, for example intravenously,intracavernosally, intramuscularly or subcutaneously; intranasally, forexample in the form of an aerosol or aqueous dispersion; by inhalation,for example as an aerosol, a nebulized aqueous dispersion or a drypowder; buccally or sublingially, for example in the form of a tablet orlozenge; topically to the skin, for example in the form of a cream orointment; or rectally, e.g. as a suppository.

In a further aspect the invention provides a pharmaceutical compositioncomprising as active ingredient a compound of formula I in free form orin the form of a pharmaceutically acceptable salt, optionally togetherwith a pharmaceutically acceptable diluent or carrier therefor. Suchcompositions may be prepared using conventional excipients andtechniques known in the galenic art. Thus oral dosage forms may includetablets and capsules. Compositions for inhalation may include aerosol orother atomizable formulations or dry powder formulations. Compositionsfor topical administration to the skin may include creams, ointments orgels.

The agents of the invention may also be used in combination with otherPDE5 inhibitors or with other therapeutic agents suitable for thetreatment of sexual dysfunction, particularly male erectile dysfunction,e.g. α adrenergic receptor antagonists such as phentolaminemethanesulfonate, dopamine D2 agonists such as apomorphine or NO donorssuch as L-arginine. An agent of the invention may be mixed with theco-therapeutic agent in a pharmaceutical composition or it may beadministered separately, before, simultaneously with or after theco-therapeutic agent.

This invention is illustrated by the following Examples.

Intermediates of formula V are prepared as follows:

Intermediate 1

Methallylamine (211 g, 2.97 mol) is added to a solution of concentratedhydrochloric acid (250 ml) in water (1.9 l), followed by portionwiseaddition of potassium cyanate (240 g, 2.97 mol). The reaction is thenheated for 2 hours at 80° C., prior to cooling and evaporation to afford(2-methyl-allyl)-urea (2445 g), mp 114-115° C. The urea (268 g, 2.35mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) inacetic anhydride, (536 ml) and the reaction is heated at 70° C. for 1hour, cooled to 0° C and diluted with ether. The resultant solid iscollected by filtration, washed with ether, suspended in water (2.2 l)and heated to 75° C. 2M aqueous sodium hydroxide solution is then addedportionwise over 30 min to maintain pH between 8 and 9.5. The reactionis cooled to room temperature, treated with acetic acid (12 ml), furthercooled to 10° C. and the resultant solid is collected by filtration,washed with cold water and dried to afford6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. Theuracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20°C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour.After standing overnight, the reaction is cooled to 5° C. and the solidcollected by filtration to give6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4dione, mp 162-163°C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) andconcentrated hydrochloric acid (72 ml). A solution of sodium nitrite(58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30minutes and the reaction is stirred at 20° C. for 3 hours. The solid iscollected by filtration, washed successively with water, methanol andether to afford6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4dione, mp213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water(950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69mol) is added portionwise. After cooling to room temperature, the solidis collected by filtration to afford5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine2,4-dione, mp152-153° C.

Intermediate 2

Using the general procedure for Intermediate 1, (3-nitrobenzyl)-urea [J.Med. Chem. 1996, 39, 1924] is converted into6-amino-3-methyl-1-(3-nitro-benzyl)-1H-pyrimidine-2,4-dione, [M−H]⁻ 275.A suspension of this compound (4.88 g, 17.7 mmol) and 10% Pd/C (0.484 g)in ethanol (200 ml) is hydrogenated at 1 atmosphere for 1.5 hours. Thereaction mixture is filtered through a celite plug and evaporated togive 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione aceticacid salt [M−H]⁻ 245. Acetic anhydride (1.85 ml, 19.57 mmol) is added toa cooled (0° C.) suspension of6-amino-1-(3-amino-beryl)-3-methyl-1H-pyrimidine-2,4-dione acetic acidsalt (5.01 g, 16.35 mmol) in pyridine (50 ml). The reaction mixture iswarmed to room temperature, stirred for 6 hours and the solventevaporated. The residue is triturated with water and the solid collectedby filtration and dried to affordN-[3-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide,¹H NMR (400 MHz, DMSO): δ: 2.00 (s 3H), 3.09 (s 3H), 4.72 (s 1H), 5.02(s 2H), 6.75 (s 2H), 6.88 (d J 6 1H), 7.25 (t J 6 1H), 7.30 (s 1H), 7.55(d J 6 1H). Using the general procedure for Intermediate 1, thiscompound is converted intoN-[3-(S,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide[MH]⁺ 304.

Intermediate 3

Using the general procedure for Intermediate 1, (4-nitro-benzyl)-urea[J. Med. Chem. 1996, 39, 1924] is converted into6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione, [MH]⁺ 277.A solution of calcium chloride (4.94 g, 45 mmol) in water (100 ml) isadded to a solution of6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione (19.08 g,69.0 mmol) in acetic acid (300 ml). Zinc dust (58.8 g, 900 mmol) is thenadded portionwise with external cooling. The reaction is stirred at roomtemperature for 1.5 hours, filtered through a celite plug and washedsuccessively with ethanol and acetic acid. Evaporation of the combinedfiltrate and washings affords6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acidsalt, [M−3H]⁻ 243. Acetic anhydride (7.2 ml, 76.0 mmol) is added to acooled (0° C.) suspension of6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine 2,4-dione acetic acidsalt (17.0 g, 69.0 mmol) in pyridine (260 ml). The reaction mixture iswarmed to room temperature, stirred for 6 hours and the solventevaporated. The residue is triturated with water and the solid collectedby filtration and dried to affordN-[4-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide,[MH]⁺ 289. Using the general procedure for Intermediate 1, this compoundis converted intoN-[4-(5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide,[MH]⁺ 304.

Intermediate 4

To 2 cooled (0° C.) slurry of 6-chloromethyluracil (2.0 g, 12 mmol) inTHF/dioxan (1:1, 16 ml) is added 2-pyridyldiphenylphosphine (3.60 g,13.7 mmol) and cyclobutanemethanol (1.3 ml, 13.8 mmol), followed bydi-t-butylazodicarboxylate (3.15 g, 13.7 mmol). The reaction is stirredovernight at ambient temperature, treated with 4M HCl in dioxan (15 ml)and evaporated. The residue is taken up in dichloromethane, washed with3.5M HCl, dried over magnesium sulfate and evaporated. The crude productis purified by flash chromatography (100:1 dichloromethanemethanolelution) to afford6-chloro-1-cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, ¹H NMR(400 MHz, CDCl₃) δ 1.70-2.0 (m 6H), 2.60 (m 1H), 3.20 (s 3H), 4.00 (d J7 2H), 5.78 (s 1H), which is dissolved in n-butanol (50 ml).Veratrylamine (4 ml, 26.5 mmol) is added and the reaction heated toreflux for 16 hours.

The solvent is evaporated and the residue taken into dichloromethane,washed with 1M aqueous HCl, dried over magnesium sulfate and evaporated.The crude product is purified by flash chromatography (50:1dichloromethane-methanol elution) to afford1-cyclobutylmethyl-6-(3,4dimethoxy-benzylamino)-3-methy-1H-pyrimidine-2,4-dione,¹H NMR (400 MHz, CDCl₃) d 1.60-1.80 (m 4H), 1.80-2.00 (m 2H), 2.50 (m1H), 3.21 is 3H), 3.80 (s 6H), 3.85 (d J 7 2H), 4.11 (d J S 1H), 4.25 (m1H), 4.84 (s 1H), 6.74 (s 1H), 6.80 (s 2H), which is dissolved in formicacid (50 ml) and Pd black (0.26 g) added. The reaction is heated at 40°C. for 21 hours, filtered through Celite, evaporated and purified bypreparative HPLC to afford6-amino-1-cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, M⁺ 209,which is converted using the general procedure for Intermediate 1 into5,6-diamino-1-cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, HPLCretention time 0.17 mins (30-95% acetonitrile water gradient in 4minutes).

Intermediate 5

5,6-Diamino-3-methyl-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrimidine-2,4-dione,mp 115-116° C., is prepared from (tetrahydro-furan-2-ylmethyl)-urea(Collect. Czech. Chem. Commun. 1972, 37, 2786) using the generalprocedure for Intermediate 1.

Intermediate 6

5,6-Diamino-3-methyl-1-(2-methyl-butyl)-1H-pyrimidine-2,4-dione, mp163-165° C., is prepared using the general procedure for Intermediate 1.

Intermediate 7

5,6-Diamino-1-hexyl-3-methyl-1H-pyrimidine-2,4-dione, is prepared from6-amino-1-hexyl-1H-pyrimidine-2,4-dione (J. Med. Chem. 1993, 36, 1465)using the general procedure for Intermediate 1, HPLC retention time(0-95% acetonitrile water gradient over 8 minutes) 6.01 min.

Intermediate 8

5,6Diamino-1-(3,4dimethoxy-benzyl)-3-methyl-1H-pyrimidine-2,4-dione,[M−H]⁻ 305, is prepared from (3,4-dimethoxy-benzyl)-urea (Farmaco, Ed.Sci. 1977, 32, 813) using the general procedure for Intermediate 1.

Intermediate 9

5,6-Diamino-1-benzo[1,3]dioxol-5-ylmethyl-3-methyl-1H-pyrimidine-2,4dione,mp 183-186° C., is prepared using the general procedure for Intermediate1.

Intermediate 10

5,6-Diamino-1-(2,4-dichloro-benzyl)-3-methyl-1H-pyrimidine-2,4 dione, isprepared using the general procedure for Intermediate 1, ¹H NMR (400 MHzDMSO-d6) δ 3.16 (s 3H), 5.05 (s 2H), 6.18 (s 2H), 6.82 (d J 9 1H), 7.38(d J 9 1H), 7.62 (s 1H).

Other Intermediates of formula V are prepared according to literaturereferences as indicated below: No. R¹ R² Reference 11 CH₃ (CH₃)₂CHCH₂(1) 12 H CH₃ (2) 13 CH₃ CH₂═CHCH₂ (3) 14 CH₃

(1) 15 CH₃ (CH₃)₃CCH₂ (1) 16 (CH₃)₂CHCH₂ (CH₃)₂CHCH₂ (1) 17 CH₃

(1) 18 H CH₃CH₂CH₂ (2) 19 CH₃

(4)References

(1) Eur. J. Med. Chem. 1990, 25, 653

(2) J. Med. Chem. 1996, 39, 2

(3) FR 2 531 085

(4) J. Med. Chem. Chem. Ther. 1974, 9, 313

Intermediates of formula VI are prepared as follows:

Intermediate 20

A mixture of, 3-(3,4-dimethoxy-phenyl)-5-nitro-pentanoic acid ethylester [J. Med. Chem, 1989, 32, 1450] (0.50 g, 1.68 mmol) andtin(II)chloride dihydrate (1.90 g, 8.4 mmol) in ethanol (10 ml) isheated to reflux for 2 hours, cooled to ambient temperature andevaporated. The crude product is taken into dichloromethane (15 ml),cooled to 0° C. and triethylamine (5 ml) added, followed by3,5-methoxybenzoyl chloride (0.404 g, 2.02 mmol). The reaction isstirred at ambient temperature overnight and then evaporated, taken intoethyl acetate, washed with water and dried over sodium sulfate.Evaporation and purification by flash column chromatography (1:1hexamethyl acetate elution) affords4-(3,5-dimethoxy-benzoylamino)-3-(3,4-dimethoxy-phenyl)-butyric acidethyl ester, [MH]⁻ 432. This intermediate (0.200 g, 0.46 mmol) is takeninto acetonitrile (8 ml) and phosphorus oxychloride (0.211 g, 1.38 mmol)added, prior to heating at reflux for 3 hours. After evaporation of thesolvent, the residue is taken into ethyl acetate, washed with saturatedaqueous sodium carbonate, dried over sodium sulfate and evaporated toafford[1-(3,5-dimethoxy-phenyl)-6,7-dimethoxy-3,4-dihydro-isoquinolin-4-yl]-aceticacid ethyl ester, [MH]⁺ 414. This intermediate (0.5 g, 1.21 mmol) isdissolved in decalin (10 ml) and 10% Pd/C (50 mg) added. The reaction isheated at 190° C. for 2.5 hours, then cooled to ambient temperature anddiluted with dichloromethane. After filtration through Celite, thecombined filtrate and washings are evaporated to afford[1-(3,5-dimethoxy-phenyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acidethyl ester, ¹H NMR (400 MHz, CDCl₃) δ 1.18 (t J 7 3H), 3.78 (s 6H),3.80 (s 3H), 3.90 (s 2H), 3.99 (s 3H), 4.10 (q J 7 2H), 6.50 (d J 0.51H), 6.75, (d J 0.5 2H), 7.20 (s 1H), 7.36 (s 1H), 8.40 (s 1H). Thisintermediate (0.30 g, 0.73 mmol) is dissolved in methanol (10 ml), 1Maqueous lithium hydroxide (0.80 ml, 0.80 mmol) is added and the reactionstirred overnight at ambient temperature. After evaporation of themethanol, pH of the residual solution is adjusted to 7 with 1M aqueousHCl and the resultant solid collected by filtration and dried to afford[1-(3,S-dimethoxy-phenyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid.

Intermediate 21

A mixture of 3-isopropoxy4-methoxy-benzaldehyde (3.9 g, 20 mmol) and(ethoxycarbonylmethylene)triphenylphosphorane (6.96 g, 20 mmol) intoluene (100 ml) is heated at reflux for 2 hours, cooled to ambienttemperature and evaporated. The crude product is taken in todichloromethane and eluted through a pad of silica to afford(E)-3-(3-isopropoxy-4-methoxy-phenyl)-acrylic acid ethyl ester, TLCR_(f) 0.70 (1:1 hexane-ethyl acetate). This intermediate is dissolved innitromethane (10 ml), 1,1,3,3-tetramethylguanidine (0.5 ml) is added andthe reaction heated at 70° C. for 36 hours. The solvent is evaporated,the residue is taken into ethyl acetate and washed with 2N aqueous HCl,water and brine. After drying over sodium sulfate and evaporation, thecrude product is purified by flash column chromatography (4:1hexane-ethyl acetate elution) to afford3-(3-isopropoxy-4-methoxy-phenyl)-4-nitro-butyric acid ethyl ester, ¹HNMR (400 MHz, CDCl₃) δ 1.20 (t J 7 3H), 1.38 (d J 7 6H), 2.75 (d J 62H), 3.90 (m 1H), 4.10 (m 2H), 4.48-4.78 (m 3H), 6.75-6.86 (m 3H). Thisintermediate is converted into[1-(3,5-diisopropoxy-phenyl)-6-isopropoxy-7-methoxy-isoquinolin4-yl)-aceticacid using the general procedure for Intermediate 20. Characterised asthe ethyl ester, [MH]⁺ 496.

Intermediate 22

A solution of 3-ethoxy-4-methoxybenzaldehyde (3.6 g, 20 mmol) in ethanol(15 ml) is added to 2,2-dimethoxyethylamine (21 mmol) and the mixtureheated at reflux for 2 hours. After cooling to room temperature, sodiumborohydride (0.794 g, 21 mmol) is added and the mixture stirred at roomtemperature overnight. Ethanol is removed by evaporation and wateradded, followed by extraction with ethyl acetate. The organic extractsare combined, washed with water, brine, dried over magnesium sulfate andevaporated to give(2,2-dimethoxy-ethyl)-(3-ethoxy-4-methoxy-benzyl)-amine, [MH]⁺ 270. Theintermediate (2.70 g, 10 mmol) is suspended in 6N HCl (50 ml), glyoxylicacid (0.88 g, 12 mmol) is added and the mixture heated for 1 hour at100° C. After cooling to room temperature, methanol (30 ml) is added andthe mixture filtered and characterised as the methyl ester M⁺ 276. Thefiltrate is treated with lithium hydroxide (10 mmol) inTHF-methanol-water overnight. After evaporation of the solvents, thecrude product is partitioned between water and dichloromethane. Theaqueous phase is washed with dichloromethane and evaporated to drynessto afford (7-ethoxy-6-methoxy-isoquinolin-4-yl)-acetic acid lithium saltwhich is used for xanthine formation without further characterisation.

Intermediate 23

A solution of (6,7-dimethoxy-isoquinolin-4-yl)-acetic acid ethyl ester(Tetrahedron 1973, 29, 3881) (1.668 g, 6.07 mmol) in chloroform (20 ml)is treated portionwise with m-chloroperoxybenzoic acid (1.153 g, 6.67mmol) for 5 hours. The reaction mixture is washed with saturated sodiumbicarbonate and brine, dried over MgSO₄ and evaporated to afford(6,7dimethoxy-2-oxy-isoquinolin-4-yl)-acetic acid ethyl ester 1.71 g,96%). The entire product is dissolved in chloroform (30 ml), added toPOCl₃ (3 ml, 32.3 mmol) and heated at reflux for 2 hours. Afterevaporation, dichloromethane and ice water are added and the mixture isbasified with aqueous ammonia. The aqueous phase is further extractedwith dichloromethane, the combined organic phases are washed with brine,dried over magnesium sulfate and evaporated to afford(1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid ethyl ester. Thechloro ester derivative (0.50 g, 1.6 mmol) is suspended in 2M sodiumhydroxide (15 ml). Ethanol (5 ml) is added and the solution stirred atroom temperature for 2 hours and the solvent evaporated. Adjustment topH 2 with concentrated hydrochloric acid affords a solid which iscollected by filtration and dried to afford(1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid. ¹H NMR (400 MHz,DMSO-d6) δ: 3.92 (s 3H), 3.96 (s 3H), 4.02 (s 2H), 7.31 (s 1H), 7.44 (s1H), 8.04 (s 1H).

Intermediate 24

(2,2-Dimethoxy-ethyl)-(3-methoxy-benzyl)-amine (Tetrahedron, 1973, 29,3881) is treated with pyruvic acid according to the general procedurefor Intermediate 22 to afford 2-(7-methoxy-isoquinolin-4-yl)-propionicacid hydrochloride salt, mp 174-176° C. Treatment with HCl gas inethanol affords the corresponding ethyl ester hydrochloride, mp 190-192°C., which is then reacted sequentially with m-chloroperoxybenzoic acidand phosphorus oxychloride as described for Intermediate 23 to provide2-(1-chloro-7-methoxy-isoquinolin-4-yl)-propionic acid ethyl ester, mp126-128° C. This intermediate (47 g, 0.16 mol) :is dissolved in ethanol(400 ml) and 2N sodium hydroxide (150 ml) added and the mixture heatedat 60° C. for one hour, prior to evaporation of the solvent.Crystallisation from acetone affords2-(1-chloro-7-methoxy-isoquinolin-4-yl)-propionic acid, mp 167-168° C.

Intermediate 25

Dimethyl sulfate (12.7 ml, 0.10 mol) is added portionwise to2-(7-methoxy-2-oxy-isoquinolin-4-yl)-propionic acid ethyl ester (28 g,0.10 mol) with an exotherm to 100° C. The reaction is maintained at thistemperature for 2 hours, cooled to room temperature and dissolved inwater (50 ml). A solution of sodium cyanide (15 g, 0.31 mol) in water(90 ml) is added over 30 minutes with external cooling and the reactionis then stirred at room temperature for 3 hours. The crude product isextracted with chloroform, the chloroform extracts are washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate andevaporated. Crystallisation from 3N ethanolic HCl-ether affords2-(1-cyano-7-methoxy-isoquinolin-4-yl)-propionic acid ethyl esterhydrochloride, mp 89-98° C. This compound is hydrolysed converted to theacid as described for Intermediate 22 and used directly crude forxanthine formation.

Intermediate 26

A solution of sodium triethylborohydride (1M THF, 12.7 ml, 12.7 mmol) isadded dropwise to a solution of isoquinoline (1.64 g, 12.7 mmol) in THF(25 ml). The reaction is stirred at room temperature for 1 hour, priorto dropwise addition of a solution of ethyl glyoxalate (1.43 g, 13.9mmol) in toluene (previously heated at 110° C. for 1.5 hours). After afurther 4 hours at room temperature, the reaction is cooled to 0° C. andsodium hydroxide (0.5 M aqueous solution, 25.4 ml) followed by hydrogenperoxide (30% aqueous solution, 12.7 ml) is added, followed by stirringfor 2 hours. The reaction is acidified with 1N HCl, washed with ethylacetate three times, the aqueous phase is reduced in volume byevaporation and refrigerated overnight. The resultant precipitate iscollected by filtration and dried to afford isoquinolin-4-yl-acetic acidhydrochloride salt, MH⁺ 188.

Intermediate 27

Excess morpholine is added to a suspension of(1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid ethyl ester (0.200g, 0.65 mmol) in toluene (1 ml) and the mixture heated to reflux untilthe starting material is consumed. After evaporation, the residue ispartitioned between water and dichloromethane, the organic phase isdried over magnesium sulfate and evaporated to afford(6,7-dimethoxy-1-morpholin-4-yl-isoquinolin-4-yl)-acetic acid ethylester [MH]⁺ 361. The crude ester (0.240 g, 0.66 mmol) is dissolved inethanol (20 ml), treated with 2M sodium hydroxide (3 ml) and stirred atroom temperature overnight. After adjustment to pH 1 with concentratedhydrochloric acid, the solvent is evaporated and the crude acid useddirectly for formation of the xanthine derivative.

Intermediate 28

The procedure for Intermediate 27 is repeated, using excessN-methylpiperazine in place of morpholine to afford[6,7-dimethoxy-1-(4-methyl-piperazin-1-yl)-isoquinolin-4-yl]acetic acidethyl ester (0.186 g, 38%) ¹H NMR (DMSO-6) δ 1.19 (t J 7 3H), 2.30 (s3H), 2.61 (m 4H), 3.10-3.30 (m 4H), 3.92 (s 6H), 3.97 (s 2H), 4.10 (q J7 2H), 7.19 (s 1H), 7.37 (s 1H), 7.91 (s 1H). The ester (0.186 g, 0.50mmol) is dissolved in ethanol (20 ml), treated with 2M sodium hydroxide(3 ml) and stirred at room temperature overnight. After adjustment to pH1 with concentrated hydrochloric acid, the solvent is evaporated and thecrude acid used directly for formation of the xanthine derivative.

Intermediate 29

N-Chlorosuccinimide (0.347 g, 2.60 mmol) is added to a solution of6-methoxyisoquinoline (Synth. Commun. 1999, 29, 1617) (0.207 g, 1.30mmol) in acetic acid (9 ml). The reaction is heated at 50° C. for 3hours, cooled to ambient temperature, evaporated and partitioned betweenethyl acetate and 1M aqueous sodium hydroxide. The organic phase iswashed with water and brine, dried over magnesium sulfate and evaporatedafford 5-chloro-6-methoxyisoquinoline, [MH]⁺ 194. A solution of thisintermediate (0.175 g, 0.90 mmol) in THF (4.5 ml) and acetic anhydride(0.101 ml, 1.08 mmol) is treated with sodium triacetoxyborohydride(0.229 g, 1.08 mmol) and the reaction is stirred at ambient temperaturefor 22 hours. The solvent is evaporated, the residue is taken into ethylacetate, washed with 0.5 M aqueous hydrochloric acid, then brine anddried over magnesium sulfate. Evaporation affords1-(5-chloro-6-methoxy-1H-isoquinolin-2-yl)-ethanone, mp 78-80° C. Asuspension of this intermediate (0.150 g, 0.60 mmol) and glyoxylic acid.(76 mg, 0.80 mmol) in 6M aqueous hydrochloric acid (2.8 ml) is heated at100° C. for 3 hours. After cooling to ambient temperature, the resultantsolid is, collected by filtration to afford(5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid, [MH]⁺ 252. Asuspension of this intermediate (0.970 g, 3.38 mmol) and ammoniumformate (1.05 g, 16.9 mmol) in 1:1 acetic acid-water (25 ml) is treatedwith 10% Pd/C (0.730 g) and stirred at ambient temperature for 16 hours.After filtration through Celite®, the combined filtrate and washings areevaporated and purified by Soxhilet extraction with acetone to afford(6-methoxy-isoquinolin-4-yl)-acetic acid [MH]⁺ 218. Alternativelyreduction of (5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid to afford(6-methoxy-isoquinolin-4-yl)-acetic acid is accomplished by stirring asuspension of (5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid (20 g,69.4 mmol) in 1 Molar sodium hydroxide solution (400 mL) for 20 min,filtering off the resultant salt and then treating with hydgrogen gas inthe presence of 10% Pd/C (1.4 g) at atmospheric pressure for 2.25 h. Theresulting suspension is filtered through glass wool and celite, washingwith water (50 mL). The solution is then cooled in an ice water bath andslowly (30 min) neutralised and then acidified with 5 Molar hydrochloricacid (80 ml). A suspension forms and further crystalisation isencouraged by standing at 5° C. for 20 h. The resulting crystals areremoved by filtration and washed with ice cold ethanol (25 ml) dryingunder reduced pressure gives (6-methoxy-isoquinolin-4-yl)-acetic acid.

Intermediate 30

Glyoxylic acid (1.37 g, 9.28 mmol) is added to mixture of1-(6-chloro-1H-isoquinolin-2yl)-ethanone (J. Org. Chem., 1980, 45, 19501(1.44 g, 5.90 mmol) in 6N HCl (24 ml). The reaction is heated at 100° C.for 3 hours, cooled to RT, washed with ether and evaporated to 10 mlvolume. After overnight refrigeration, the solid is collected byfiltration and dried to afford (6-chloro-isoquinolin-4-yl)-acetic acidhydrochloride. ¹H NMR (400 MHz, DMSO) δ: 4.45 (s 2H), 8.18 (d J 9 1H),8.52 (s 1H), 8.70 (d J 8 1H), 8.83 (s1H), 9.96 (s 1H).

Intermediate 31

Sodium borohydride (1.12 g, 29.6 mmol) is added portionwise to a cooled(0° C.) solution of 6-bromoisoquinoline [J Chem Soc Perkin Trans 2,1998, 437] (1.544 g, 7.42 mmol) in acetic acid (10 ml) and aceticanhydride (3 ml). After heating at 60° C. for 4 hours, the mixture iscooled, evaporated and diluted with water. After adjustment to pH10 withpotassium carbonate and extraction with ethyl acetate, the combinedorganic phases are washed twice with 0.5N HCl and brine, then dried oversodium sulphate. Evaporation affords1-(6-bromo-1H-isoquinolin-2-yl)-ethanone, MH⁺ 253. Glyoxylic acid (0.812g, 8.80 mmol) is added to mixture of1-(6-bromo-1H-isoquinolin-2-yl)-ethanone (1.50 g, 5.90 mmol) in 6N HCl(20 ml). The reaction is heated at 100° C. for 2 hours, cooled to RT andwashed with ethyl acetate. After evaporation, the residue is taken intomethanol (20 ml), concentrated sulphuric acid (10 drops) is added andthe mixture heated at reflux for 14 hours. After partial evaporation ofthe solvent, the resultant solid is collected by filtration, washed withmethanol and dried to afford (6-bromo-isoquinolin-4-yl)-acetic acidmethyl ester hydrochloride, MH⁺ 281. Lithium hydroxide hydrate (8.5 mg,0.20 mmol) is added to a cooled (0° C.) solution of(6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (50 mg, 0.18 mmol)in 3:1 THF-water (3 ml). After 1 hour the solvent is evaporated toafford (6-bromo-isoquinolin-4-yl)-acetic acid lithium salt, MH⁺ 266.

Intermediate 32

Trimethylsilylacetylene (0.17 ml, 1.23 mmol) is added to a suspension of(6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (0.325 g, 1.03 mmol)in DMF (1.75 ml) and triethylamine (10 ml), follwed by copper(I) iodide(40 mg, 0.20 mmol) and (Ph₃P)₂PdCl₂ (73 mg, 0.10 mmol). The reaction isheated at 45° C. for 40 minutes, cooled to ambient temperature anddiluted with ethyl acetate. After washing with water and brine, theorganic phase is dried over, magnesium sulfate, evaporated and purifiedby flash column chromatography (1:1 ethyl acetate-hexane elution) toafford (6-trimethylsilanylethynyl-isoquinolin-4-yl)-acetic acid methylester, [MH]⁺ 298. This intermediate (0.221 g, 0.74 mmol) is dissolved inmethanol (7.5 ml) and treated with potassium carbonate (75 mg, 0.54mmol). The reaction is stirred for 30 minutes at ambient temperature,evaporated and purified by flash chromatography (5:1dichloromethane-methanol elution) to afford(6-ethynyl-isoquinolin-4-yl)-acetic acid, [MH]⁺ 212.

Intermediate 33

Bromine (0.211 mi, 6.28 mmol) in dichloromethane (10 ml) is added to acooled (0° C.) solution of 6-methoxyisoquinoline [Synth. Commun. 1999,29, 1617] and the reaction is stirred at ambient temperature for 20hours. After pouring into 1M aqueous sodium hydroxide, the organic phaseis washed with brine, dried over magnesium sulfate and evaporated. Thecrude product is purified by flash column chromatography (20:1dichloromethane-methanol elution) to afford5-bromo-6-methoxyisoquinoline, [MH] 240. This material is then convertedaccording to the procedure for Intermediate 29 into(5-bromo-6-methoxy-isoquinolin4-yl)-acetic acid [MH]⁺ 298.

Intermediate 34

[1-(3,5-Diisopropoxy-phenyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acidis prepared using the general procedure for Intermediate 20, ¹H NMR (400MHz CDCl₃) δ 1.25 (d J 6 12H), 3.78 (s 3H), 3.86 (s 2H), 3.92 (s 3H),6.46 (d J 0.5 1H), 6.65 (d J 0.5 2H), 7.20 (s 2H), 8.30 (s 1H).

The following are prepared analogously to Intermediate 21:

Intermediate 35:1-(3,5-Dimethoxy-phenyl)-6-isopropoxy-7-methoxy-isoquinolin-4-yl]-aceticacid, [MH]⁺ 412.

Intermediate 36:(1-.tert.-Butyl-6-isopropoxy-7-methoxy-isoquinolin-4-yl)-acetic acid, ¹HNMR (400 MHz, CDCl₃) δ 1.32 (d J 7 6H), 1.52 (s 9H), 3.80 (s 2H), 3.90(s 3H), 4.75 (heptet J 7 1H), 7.28 (s 1H), 7.66 (s 1H), 8.08 (s 1H).

Intermediate 37:(6-Isopropoxy-1-isopropyl-7-methoxy-isoquinolin-4-yl)-acetic acid, [MH]⁺318.

The following are prepared analogously to Intermediate 20:

Intermediate 38: (6,7-Dimethoxy-1-methyl-isoquinolin-4-yl)acetic acid,[MH]⁺ 262.

Intermediate 39: (1-tert.-Butyl-6,7-dimethoxy-isoquinolin-4-yl)-aceticacid, ¹H NMR (400 MHz, CDCl₃) d 1.75 (s 9H), 3.95 (s 6H), 4.04 (s 2H),7.28 (s 1H), 7.75 (s 1H), 8.66 (s 1H).

Intermediate 40: (1-Isopropyl-6,7-dimethoxy-isoquinolin-4-yl)-aceticacid, characterised as the ethyl ester ¹H NMR (400 MHz, CDCl₃) δ 1.25 (tJ 7 3H), 1.45 (d J 7 3H), 3.82 (heptet J 7 1H), 3.90 (s 2H), 3.08 (s2H), 4.15 (q J 7 2H), 7.28 (s 1H), 7.48 (s 1H), 8.30 (s 1H).

Intermediate 41: 2-(7Methoxy-1-morpholin-4-yl-isoquinolin4-yl)-propionicacid mp 225-227° C., is prepared according to the procedure forIntermediate 27.

The following are prepared analogously to Intermediate 22:

Intermediate 42: [MH]⁺ 332 (7-Hydroxy-6-methoxy-isoquinolin-4-yl)-aceticacid lithium salt, via(3-benzyloxy-4-methoxy-benzyl)-(2,2-dimethoxy-ethyl)-amine.

Intermediate 43: (6,7-Dimethoxy-3-methyl-isoquinolin-4-yl)-acetic acid,¹H NMR (400 MHz, DMSO) δ: 2.50 (s 3H), 3.91 (s 3H), 3.93 (s 3H), 4.02 (s2H), 7.30 (s 1H), 7.43 (s 1H), 8.30 (s 1H).

Intermediate 44: (6-Ethoxy-7-methoxy-isoquinolin-4-yl)-acetic acid, 3 M⁺261.

The following are prepared analogously to Intermediate 22, using pyruvicacid in place of glyoxylic acid:

Intermediate 45: 2-(6-Ethoxy-7-methoxy-isoquinolin-4-yl)propionic acidlithium salt, characterised as the methyl ester, M⁺ 290.

Intermediate 46: 2-(7-Ethoxy-6-methoxy-isoquinolin-4-yl)-propionic acidlithium salt, characterised as the methyl ester, M⁺ 290.

Intermediate 47: 2-(6,7-dimethoxy-isoquinolin-4-yl)-propionic acid,characterised as the methyl ester, M⁺ 276.

Intermediate 48: 8-Fluoro-6-methoxy-isoquinolin-4-yl)-acetic acid, isprepared according to the procedure for Intermediate 31 andcharacterised as the methyl ester, [MH]⁺ 250.

Intermediate 49: (6,7-dimethoxy-isoquinolin-4-yl)-acetic acid, andIntermediate 50, [1,3]dioxolo[4,5-.g.]isoquinolin-8-yl-acetic acid, areprepared as described in Dyke et al, Tetrahedron 1968,24, 1467.

Intermediate 51: (7-methoxy-isoquinolin-4-yl)-acetic acid is preparedaccording to Dyke et al, Tetrahedron, 1973,29, 3881.

Intermediate 52: 2,2-Dimethoxyethylamine (13.85 ml, 0.13 mol) is addedto a solution of 3-fluoro-4-methoxybenzaldehyde (20 g, 0.13 mol) intoluene (200 ml). The resulting solution is flushed with nitrogen gasand then heated overnight under reflux in a Dean-Stark apparatus. Thesolvent is then removed under reduced pressure to yield(2,2-dimethoxy-ethyl)-[1-(3-fluoro-4-methoxy-phenyl)-methylidene]-amine.This intermediate (31 g, 0.13 mol) is dissolved in ethylacetate andacetic anhydride (13.1 g, 0.13 mol) added. Platinum oxide (0.3 g) isthen added, under a blanket of nitrogen, and the resulting mixture isstirred under a hydrogen atmosphere until uptake is complete.Filtration, washing with saturated aqueous NaHCO₃ (3×100 ml), brine andwater, drying over MgSO₄ and concentration then givesN-(2,2-dimethoxy-ethyl)-N-(3-fluoro-4-methoxy-benzyl)-acetamide. Thisintermediate (38.9 g, ca 0.13 mol) is dissolved in anhydrous CH₂Cl₂ andthen added slowly over 20 mins to a stirred nixture of AlCl₃ (90 g) andCH₂Cl₂ under an atmosphere of nitrogen. The total volume of CH₂Cl₂ is250 ml. The mixture is stirred for a further 10 mins at room temperatureand is then cooled with an ice bath during the addition of aqueous 40%NaOH. The mixture is further diluted with water (250 ml), filteredthrough glass wool, the organic phase separated and the aqueous phasefurther extracted with CH₂Cl₂ (2×200 ml). Drying over MgSO₄ andevaporation under reduced pressure yields a crude oil which is purifiedby flash silica chromatography (eluant: 1% methanol in CH₂Cl₂) to giveas one of the products1-(7-fluoro-6-methoxy-1H-isoquinolin-2-yl)-ethanone. This intermediate(0.60 g, 2.7 mmol) is mixed with glyoxylic acid (0.325 g, 3.5 mmol) andwater (10 ml) and the resulting mixture is stirred at room temperaturefor 20 min. Concentrated hydrochloric acid (10 ml) is then added and themixture heated to reflux for 1 h. Concentration and purification bypreparative HPLC gives (7-fluoro-6-methoxy-isoquinolin-4-yll)-aceticacid, [MH]⁺ 236.

The following are prepared analogously to Intermediate 20:

Intermediate 53: (1-Methyl-6-methoxy-isoquinolin-4-yl)-acetic acid.

Intermediate 54: (6-Isopropoxy-1-methyl-isoquinolin-4-yl)-acetic acid.

Intermediate 55: (6-Ethoxy-1-methyl-isoquinolin-4-yl)-acetic acid.

Intermediate 56: A solution of (6-bromo-isoquinolin-4-yl)-acetic acidmethyl ester (52 mg, 0.19 mmol), prepared as described as anintermediate for Intermediate 31, in DMF (3 ml) is added to zincdicyanide (26 mg, 0.2 mmol) under a nitrogen atmosphere. To theresulting mixture is added 1,1′-bis(diphenylphosphino)ferrocene (15 mg)and tris(dibenzylideneacetone)dipalladium(0) (8 mg) and the resultingmixture stirred at 120° C. for 22 h. The solution is cooled and dilutedwith chloroform (30 ml) and washed with water (2×20 ml) followed bybrine (20 ml). Further chloroform is added (40 ml) and the solutiondried over MgSO₄, filtered and concentrated. Repetitive flash silicacolumn chromatography (eluants 40:1 CH₂Cl₂:methanol, then 50:1CH₂Cl₂:methanol) gives (6-cyano-isoquinolin-4-yl)-acetic acid methylester [MH]⁺ 227. This intermediate is saponified by treatment with LiOHin 3:1 THF/water. The resulting mixture is partially evaporated toremove the THF, diluted to 10 ml with water then washed with ethylacetate. The aqueous phase is then neutralised with 1M hydrochloric acid(to pH 4-5) and exhaustively extracted with ethylacetate. The organicphase is dried over MgS0₄, filtered and concentrated to give(6-cyan-isoquinolin-4-yl)-acetic acid M⁺ 212.

Intermediate 57: (5-Chloro-6-methoxy-isoquinolin-4-yl)-acetic acid isprepared as described in the procedure for intermediate 29.

Intermediate 58: To a solution of(6-trimethylsilanylethynyl-isoquinolin-4-yl)-acetic acid methyl ester,as prepared for Intermediate 32 (0.19 g, 0.64 mmol), in anhydrousmethanol (7 ml) is added K₂CO₃ (72 mg) and the resulting mixture stirredfor, 1 h. Additional K₂CO₃ (11 mg) is then added and stirring continuedfor 30 min. The mixture is then neutralised with glacial acetic acid andconcentrated. Purification by flash silica column chromatography(ethylacetate/hexane 1:1) gives (6-ethynyl-isoquinolin-4-yl)-acetic acidmethyl ester M⁺ 225. This intermediate (79 mg, 0.35 mmol) is dissolvedin methanol under an inert atmosphere and 10% Pd on carbon (79 mg)added. The resulting suspension is stirred vigorously under anatmosphere of gaseous hydrogen. After 90 mins, filtration, washing withmethanol and concentration give (6-ethyl-isoquinolin-4-yl)-acetic acidmethyl ester M⁺ 229. To a solution of this intermediate (68 mg, 0.30mmol) in THF/methanol/water (3:1:1, 3.5 ml) is added LiOH (12.5 mg) andthe mixture stirred for 20 h at room temperature. Concentration underreduced pressure gives lithium (6-ethyl-isoquinolin-4-yl)-acetate M⁺221.

Intermediate 59: A solution of Intermediate 29 (0.5 g, 2.3 mmol) issuspended in aqueous 48% HBr (10 ml) and then heated at 100° C. for 48h. Further aqueous 48% HBr (10 ml) is then added and heating continuedat 100° C. for an additional 24 h. The reaction mixture is cooled to 5°C. for 4 h and the resulting solid separated by filtration. Washing withwater and drying under high vacuum at 50° C. gives(6-hydroxy-isoquinolin-4-yl)-acetic acid hydrobromide [MH]⁺ 204.4. Thisintermediate (0.15 g, 0.53 mmol) is suspended in DMF (2 ml) and K₂CO₃(0.22 g, 1.58 mmol) added followed by ethyliodide (0.085 ml, 1.06 mmol)and the resulting mixture stirred at room temperature for 2 h.Concentration and purification by flash silica column chromatography(eluant: CH₂Cl₂/methanol 10:1) gives (6-ethoxy-isoquinolin-4-yl)-aceticacid ethyl ester [MH]⁺ 260. This intermediate (25 mg, 0.11 mmol) isdissolved in water (1 ml) and LiOH added (5 mg, 0.11 mmol). Theresulting mixture is stirred for 30 min at room temperature.Acidification with minimum 6N HCl and concentration gives crude(6-ethoxy-isoquinolin-4-yl)acetic acid.

EXAMPLES 1-70

Compounds of formula I which are also of formula

where R¹ to R⁴ and R⁸ to R¹³ are as hereinbefore defined, in free orsalt form, and their methods of preparation are shown in the followingtable, the methods being described hereinafter. R³ is H in all Examplesexcept No 44, where it is CH₃. R⁴ is H in all examples except Nos 25-27and 41-43, where it is CH₃. R⁹ is H in all Examples except No 29, whereit is CH₃. R¹⁰ is H in all Examples except No 57, where it is Br and No75 where it is Cl. R¹³ is H in all Examples except Nos 56 where it is F,and 65 and 66, where it is Br. React- ing Inter- Ex. m/z medi- No. R¹ R²R⁸ R¹¹ R¹² MH+ MH− Method ates 1 CH₃ (CH₃)₂CHCH₂

OCH₃ OCH₃ 560 A 11 + 20 2 CH₃ (CH₃)₂CHCH₂

OCH₃ OCH₃ 616 A 11 + 34 3 CH₃ (CH₃)₂CHCH₂

OCH(CH₃)₂ OCH₃ 644 A 11 + 21 4 CH₃ (CH₃)₂CHCH₂

OCH(CH₃)₂ OCH₃ 588 A 11 + 35 5 CH₃ (CH₃)₂CHCH₂ (CH₃)₃C OCH(CH₃)₂ OCH₃508 A 11 + 36 6 CH₃ (CH₃)₂CHCH₂ (CH₃)₂CH OCH(CH₃)₂ OCH₃ 494 A 11 + 37 7CH₃ (CH₃)₂CHCH₂ CH₃ OCH₃ OCH₃ 437 A 11 + 38 (M+) 8 CH₃ (CH₃)₂CHCH₂ (CH₃₎₃C OCH₃ OCH₃ 480 A 11 + 39 9 CH₃ (CH₃)₂CHCH₂ (CH₃)₂CH OCH₃ OCH₃ 465 A11 + 40 (M+) 10 CH₃ (CH₃)₂CHCH₂ H OCH₃ OCH₃ 424 C 11 + 49 11 CH₃

H OCH₃ OCH₃ 513 A  2 + 49 12 H CH₃ H OCH₃ OCH₃ C 12 + 49 13 CH₃CH₂═CHCH₂ H OCH₃ OCH₃ C 13 + 49 14 CH₃

H OCH₃ OCH₃ C 14 + 49 15 CH₃ (CH₃)₃CCH₂ H OCH₃ OCH₃ C 15 + 49 16(CH₃)₂CHCH₂ (CH₃)₂CHCH₂ H OCH₃ OCH₃ C 16 + 49 17 CH₃

H OCH₃ OCH₃ C 17 + 49 18 CH₃ CH₂═C(CH₃)CH₂ H OCH₃ OCH₃ C  1 + 49 19 CH₃

H OCH₃ OCH₃ C  5 + 49 20 CH₃

H OCH₃ OCH₃ C  6 + 49 21 H CH₃CH₂CH₂ H OCH₃ OCH₃ C 18 + 49 22 CH₃

H OCH₃ OCH₃ 515 C  3 + 49 23 CH₃ (CH₃)₂CHCH₂ H

C 11 + 50 24 CH₃ (CH₃)₂CHCH₂ H H OCH₃ 394 C 11 + 51 25 CH₃ (CH₃)₂CHCH₂Cl H OCH₃ 442 C 11 + 24 26 CH₃ (CH₃)₂CHCH₂ CN H OCH₃ 433 C 11 + 25 27CH₃ (CH₃)₂CHCH₂

H OCH₃ 493 C 11 + 41 28 CH₃ (CH₃)₂CHCH₂ H OCH₃ OH 410.7 D 11 + 42 29 CH₃(CH₃)₂CHCH₂ H OCH₃ OCH₃ 438.6 D 11 + 43 30 CH₃ CH₃(CH₂)₅ H OCH₃ OCH₃452.8 D  7 + 49 31 CH₃

H OCH₃ OCH₃ 518.4 D  8 + 49 32 CH₃

H OCH₃ OCH₃ 502.4 D  9 + 49 33 CH₃

H OCH₃ OCH₃ 527.8 D 10 + 49 34 CH₃

H OCH₃ OCH₃ 487.9 D 19 + 49 35 CH₃ (CH₃)₂CHCH₂ Cl OCH₃ OCH₃ 458.4 D 11 +23 36 CH₃ (CH₃)₂CHCH₂ H H H 364 C 11 + 26 37 CH₃ (CH₃)₂CHCH₂ H OCH₂CH₃OCH₃ 438 C 11 + 44 38 CH₃ (CH₃)₂CHCH₂

OCH₃ OCH₃ 509.1 D 11 + 27 39 CH₃ (CH₃)₂CHCH₂

OCH₃ OCH₃ 522.02 D 11 + 28 40 CH₃ (CH₃)₂CHCH₂ H OCH₃ OCH₂CH₃ 438 C 11 +22 41 CH₃ (CH₃)₂CHCH₂ H OCH₂CH₃ OCH₃ 452 C 11 + 45 42 CH₃ (CH₃)₂CHCH₂ HOCH₃ OCH₂CH₃ 452 C 11 + 46 43 CH₃ (CH₃)₂CHCH₂ H OCH₃ OCH₃ 438 C 11 + 4744 CH₃ (CH₃)₂CHCH₂ H OCH₃ OCH₃ 438 J — 45 CH₃ (CH₃)₂CHCH₂ H OCH₃ H 394B2 11 + 29 46 CH₃

H OCH₃ H 408 C  6 + 29 47 CH₃ (CH₃)₃CCH₂ H Cl H 410 C 15 + 30 48 CH₃(CH₃)₂CHCH₂ H Cl H 396 C 11 + 30 49 CH₃

H OCH₃ H C 14 + 29 50 CH₃

H Cl H 394 C 14 + 30 51 CH₃

H OCH₃ OCH₃ 436.6 434.5 B1  4 + 49 52 CH₃ CH₂═C(CH₃)CH₂ H OCH₃ H 392 390C  1 + 29 53 CH₃ (CH₃)₂CHCH₂ H Br H 441 C 11 + 31 54 CH₃ (CH₃)₃CCH₂ HOCH₃ H 408 C 15 + 29 55 CH₃ (CH₃)₂CHCH₂ H C≡CH H 388 B1 11 + 32 56 CH₃(CH₃)₂CHCH₂ H OCH₃ H 412 C 11 + 48 57 CH₃ (CH₃)₂CHCH₂ H OCH₃ H 473 C11 + 33 58 CH₃

H OCH₃ OCH₃ E — 59 CH₃

H OCH₃ OCH₃ F — 60 CH₃

H OCH₃ OCH₃ 580 F — 61 CH₃

H OCH₃ OCH₃ 578 (M+) F — 62 CH₃

H OCH₃ OCH₃ 473 E — 63 CH₃ (CH₃)₂CHCH₂ H H OH 379 G — 64 CH₃ (CH₃)₂CHCH₂H OH OH 396 G — 65 CH₃ (CH₃)₂CHCH₂ H OH OH 474 H — 66 CH₃ (CH₃)₂CHCH₂ HH OH H — 67 CH₃ HO(CH₂)₃ H OCH₃ OCH₃ 426 I — 68 CH₃

H OCH₃ OCH₃ 440 I — 69 CH₃

H OCH₃ OCH₃ 482 K — 70 CH₃

H OCH₃ OCH₃ 436 L — 71 CH₃

H OCH₃ H 434 B1 17 + 29 72 CH₃

H OCH₃ H 422 B1  5 + 29 73 CH₃ (CH₃)₂CHCH₂ H OCH₃ F 412 410 B1 11 + 5274 CH₃ (CH₃)₂CHCH₂ H CO₂H H 408 C 11 + 56 75 CH₃ (CH₃)₂CHCH₂ H OCH₃ H428 B1 11 + 57 76 CH₃ (CH₃)₂CHCH₂ H CN H 389 M 77 CH₃ (CH₃)₂CHCH₂ HCH₂CH₃ H 392 B1 11 + 58 78 CH₃ (CH₃)₂CHCH₂ H OCH₂CH₃ H 408.54 B1 11 + 5979 CH₃

H OCH₃ H 443.44 B1 + E  3 + 29 80 CH₃

H OCH₃ H 549 547 F 81 CH₃

H OCH₃ H 549 M⁺ F 82 CH₃ (CH₃)₂CHCH₂ N(CH₂)₃ OCH₃ OCH₃ 467 465 N 11 + 2383 CH₃ (CH₃)₂CHCH₂

OCH₃ OCH₃ 507 505 O 11 + 23 83 CH₃ (CH₃)₂CHCH₂ CH₃ OCH₃ H 408 406 A 11 +53 84 CH₃ (CH₃)₂CHCH₂ CH₃ OCH(CH₃)₂ H M⁺ 435 A 11 + 54 85 CH₃(CH₃)₂CHCH₂ CH₃ OCH₂CH₃ H 422 420 A 11 + 55Method A

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.201 g,1.30 mmol) is added to5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.223 g, 1.05mmol)) and (6,7-dimethoxy-1-methyl-isoquinolin-4-yl)-acetic acid (0.25g, 0.96 mmol) in methanol (5 ml) and water (1 ml) and the mixture isstirred at ambient temperature for 16 hours. The methanol is evaporatedand the resultant solid collected by filtration, taken into methanol (5ml) and 5M aqueous sodium hydroxide (0.5 ml) is added. The reaction isheated to reflux for 1 hour, cooled to ambient temperature andevaporated. The residue is dissolved in water and extracted withdichloromethane, the combined organic extracts are dried over sodiumsulfate and evaporated to afford8-(6,7-dimethoxy-1-methyl-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione,M⁺ 437.

Method B1

(6-Ethynyl-isoquinolin-4-yl)-acetic acid (58 mg, 0.28 mmol) is dissolvedin DMF (1 ml) and O-(7-azabenzotriazo-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphatc (0.125 g, 0.33 mmol) and Hunig's base (0.180 ml,1.03 mmol) are added, followed by a solution of5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (58 mg, 0.28mmol) in DMF (0.7 ml). The reaction is stirred at room temperature for 2hours. The solvent is evaporated and the residue purified by flashcolumn chromatography (30:1 dichloromethane-methanol elution). Theintermediate is dissolved in methanol (2 ml) and water (2.75 ml) added,followed by 4M aqueous sodium hydroxide (0.25 ml). The reaction isheated at 40° C. for 2 hours, then stirred for 16 hours at ambienttemperature. The solvent is evaporated and the crude product purified byflash column chromatography (30:1 dichloromethane-methanol elution) toafford8-(6-ethynyl-isoquinolin-4-ylmethyl)-3-isobutyl-methyl-3,7dihydro-purine-2,6-dione,[MH]⁺ 388.

Method B2

A suspension of (6-methoxy-isoquinolin-4-yl)-acetic acid (3.5 g, 13.82mmol) in acetonitrile (70 ml) is treated sequentially with Hunig's base(6.15 ml, 36 mmol), O(7-benzotriazo-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (6.29 g, 16.6 mmol) and5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (3.22 g, 15.2 atmmol) while the solution is stirred at room temperature. The reaction isstirred at ambient temperature for 2 h, prior to evaporation of thesolvent. The residue is triturated with ethyl acetate (50 ml) filteredand washed with ethyl acetate and then dried at 50° C. under reducedpressure. The resulting intermediate is suspended in a mixture ofmethanol (30 ml) and 4M aqueous sodium hydroxide (60 ml) and heated at80° C. for 45 minutes. This suspension is neutralised with acetic acidand cooled to 0-5° C. overnight. The resultant solid is collected byfiltration, and washed with methanol/water 1:9 (30 ml) followed bymethanol (30 ml). Drying under high vacuum at 550° C. affords3-isobutyl-8-(6-methoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione,[MH]⁺ 394.5.

Method C

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.6Maqueous solution, 0.33 ml, 1.85 mmol) is added to a suspension of5,6-diamino-1-isobutyl-3-methyl-1H pyrimidine-2,4-dione (0.327 g, 1.54mmol), (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid (0.414 g,1.54 mmol) and 1-hydroxybenzotriazole (0.251 g, 1.85 mmol) in CH₂Cl₂ (2ml). Water (2 ml) is added, the biphasic mixture is shaken for 18 hoursand the the resultant solid is collected by filtration. Thisintermediate is suspended in methanol (10 ml), 4M aqueous NaOH (5 ml) isadded and the mixture heated to reflux for 4 hours. After evaporation ofthe methanol, the residue is acidified to pH2 with concentratedhydrochloric acid and the resultant solid collected by filtration andpurified by preparative HPLC to afford8(1-chloro-6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dionehydrochloride, [M]⁺ 458.

Method D

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (20.6 ml, 0.1 mol) isadded to a mixture of5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (20 g, 0.094mol), (5,6-dimethoxy-isoquinolin-4-yl)-acetic acid (26.7 g, 0.094 mol),and 1-hydroxybenzotriazole (19.2 g, 0.142 mol) in 1:1dichloromethane-water (400 ml). The reaction is stirred at ambienttemperature for 4.5 hours and the resultant solid collected byfiltration. Slurrying in water (500 ml), filtration and washing withwater (250 ml) followed by drying, further trituration with methanol anddrying gives an intermediate together with slightly less pure materialfrom concentration of the methanol triturate. The intermediate (16.08 g)is dissolved in water (100 ml) and methanol (100 ml) followed by theaddition of 4M aqueous sodium hydroxide (56 ml) and the resultantsolution is heated at 70° C. over night. After cooling to ambienttemperature, the methanol is evaporated and the residue acidified to pH1 with concentrated hydrochloric acid. The resultant hydrochloride saltis collected by filtration and dried. The product is then be convertedto the free base by treatment with aqueous sodium hydroxide to pH 11 andwashing with water to afford3-isobutyl-8-(5,6-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione[MH]⁺ 424.6.

Method E

A suspension of the product of Example 11 (72 mg, 0.13 mmol) in 6N HCl(25 ml) and ethanol (1.5 ml) is heated to reflux for 5 hours then stoodat room temperature overnight. The resultant precipitate is collected byfiltration, washed with water and dried to afford3-(3-amino-benzyl)8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione dihydrochloride, ¹H NMR(400 MHz, DMSO) δ: 3.20 (s 3H), 3.95 (s 3H), 4.00 (s 3H), 4.75 (s 2H),5.15 (s 2H), 7.15 (m 2H), 7.20 (s 1H), 7.30 (t J 6 1H), 7.65 (s 1H),7.95 (s 1H), 8.50 (s 1H), 9.50 (s 1H), 13.6 (br s 1H).

Method F

The product of Example 58 (37 mg, 0.07 mmol) is suspended in pyridine(1.5 ml) and dimethylsulfarmoyl chloride (23 ml, 0.21 mmol) is added.The reaction is heated at 50° C. for 22 hours and the solvent isevaporated. Trituration with water gives a solid which is collected byfiltration and dried to afford3-[3-(N,N-dimethylsulfarmoyl)aminobenzyl]-8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione,¹H NMR (400 MHz, DMSO) δ: 2.64 (s 6H), 3.26 (s 3H), 3.86 (s 3H), 3.98 (s3H), 4.50 (s 2H), 5.15 (s 2H), 6.98 (d J 6 1H), 7.08 (d J 6 1H), 7.15 (s1H), 7.22 (t 6 3H), 7.55 (s 1H), 7.62 (s 1H), 8.38 (s 1H), 9.15 (s 1H),9.82 (s 1H), 13.60 (s 1H).

Method G

The product of Example 24 (100 mg, 0.25 mmol) is heated at 100° C. inconcentrated hydrobromic acid (5 ml) for 36 hours. The solvent isevaporated and the crude product purified by preparative HPLC to afford8-(7-hydroxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione,[M]⁺ 379.

Method H

The product of Example 64 (41 mg, 0.09 mmol) is dissolved in acetic acid(2 ml) and treated with bromine in acetic acid (148 mg/ml solution: 100μl). After 1 hour at room temperature the solvent is evaporated, theresidue dissolved in hot methanol, filtered and evaporated to afford8-(8-bromo-6,7-dihydroxisoquinolin-4-ylmethyl)3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione,M⁺ 474.

Method I

A suspension of the product of Example 13,3-allyl-8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6dione-hydrochloride salt (0.760 g, 1.87 mmol), 9-borabicyclo[2.2.0]nonane(0.5M THF solution, 18.7 ml, 9.35 mmol) and diisopropylethylamine (0.33ml, 1.89 mmol) in THF (9 ml) is heated to reflux for 2.5 hours. Sodiumhydroxide (4M aqueous solution, 6 ml) and hydrogen peroxide (27.5%, 3ml) are added sequentially and the reaction heated at 50° C. for 1.5hours. After evaporation, the crude product is purified by flashchromatography (19:1 CH₂Cl₂:methanol elution) and triturated with waterto afford8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-(3-hydroxy-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione,[MH]⁺ 426.

Method J

Potassium carbonate (48 mg, 0.35 mmol) and iodomethane (0.018 ml,0.295mmol) are added to a solution of the product of Example 10,8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione(0.100 g, 0.24 mmol) in DMF (2 ml). The reaction is stirred overnightand purified by preparative HPLC to afford8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1,7-dimethyl-3,7-dihydro-purine-2,6-dione,[MH]⁺ 438.

Method K

A suspension of the product of Example 68,8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-(3-hydroxy-2-methyl-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione(63 mg, 0.144 mmol) and acetyl chloride (18 ml, 0.25 mmol) in pyridine(1 ml) is heated at 50° C. for 18 hours. After evaporation, flashchromatography (19:1 dichloromethane-methanol elution) affords aceticacid3-[8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-2,6dioxo-1,2,6,7-tetrahydro-purin-3-yl]-2-methyl-propylester, [MH]⁺ 482.

Method L

The product of Example 18,8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3-(2-methyl-allyl)-3,7-dihydro-purine-2,6-dione(100 mg, 0.24 mmol) is suspended in 1,2-dichloroethane (30 ml). Diethylzinc (1M hexane solution, 1.2 ml, 120 mmol) is added, followed bychloroiodomethane (0.174 ml, 0.24 mmol) and the reaction is stirred atambient temperature for 1 hour, prior to quenching with saturatedaqueous NH₄Cl. After extraction with chloroform, the organic, phase iswashed with water, dried over MgSO₄ and evaporated. Purification bypreparative HPLC affords8-(6,7-methoxy-isoquinolin-4-ylmethyl)-1-methyl-3-(1-methylcyclopropylmethyl)-3,9-dihydro-purine-2,6-dione,[MH]⁺ 436.

Method M

The product of Example 53,8-(6-bromo-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione(245 mg, 0.554 mmol) is dispersed in a mixture of triethylamine (0.085ml, 0.61 mmol) and CH₂Cl₂ (4 ml). To the stirred mixture is addeddropwise a solution of di-tert butoxycarbonate (133 mg, 0.61 mmol) inCH₂Cl₂(1 ml); after 2 h triethylamine (0.170 ml, 1.2 mmol), di-tertbutoxycarbonate (130 mg, 0.60 mmol) and DMF (0.3ml) are added and themixture is stirred at room temperature for 25 days. Concentration,partitioning between water and hexane, sonification filtration,re-concentration followed by purification by flash silica columnchromatography (eluant 19:1 CH₂Cl₂: methanol) gives8-(6-bromo-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl2,6dioxo-1,2,3,6-tetrahydro-purine-7-carboxylicacid .tert.-butyl ester ([MH]⁺ 543). This intermediate (58 mg, 0.11mmol) is added to Zn(CN)₂ (15 mg, 0.13 mmol) followed by1,1′-bis(diphenylphosphino)ferrocene (9 mg), tris(dibenzylideneacetone)dipalladium(0) (5 mg) and anhydrous DMF (2.5 ml) and the resultingmixture stirred at 120° C. for 18 h and then for a further 24 h at 150°C. Zn(CN)₂ (57 mg, 0.49 mmol) and anhydrous DMF (1 ml) are then addedand the mixture is heated for 2 h at 155° C. for 2 h followed by 18 h at145° C. 1,1′-Bis(diphenylphosphino)ferrocene (9 mg), tris(dibenzylideneacetone)dipalladium(0) (9 mg) are then added and thereaction is heated for a further 6 h at 145° C. Concentration,trituration with water, filtration, washing with 1:1 saturatedNaHCO₃/water, followed by extraction with CH₂Cl₂ and 1:1 methanol:CH₂Cl₂ and repetitive flash silica column chromatography eluants 10:1CH₂Cl₂:methanol then 20:1 CH₂Cl₂:methanol) gives4-(3-isobutyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl)-isoquinoline-6-carbonitrile[MH]⁺ 389.

Method N

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.29 g, 1.9mmol) is added to5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.40 g, 1.9mmol)) and (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid (0.39g, 1.78 mmol) in methanol and water and the mixture is stirred atambient temperature for 2 hours. The methanol is evaporated and theresultant solid collected by filtration and recrystalised fromethylacetate/methanol. The resulting solid is heated in a sealed tube(100° C., 8 h) with 40% aqueous dimethylamine. The mixture is evaporatedand extracted with ethylacetate. The ethylacetate solution is thenwashed with water and brine, dried over sodium sulphate, filtered andconcentrated. Further purification by flash silica column chromatography(eluant: ethylacetate/methanol) yields8-(1-dimethylamino-6,7-dimethoxy-isoquinolin-4-ylmethyl)3-isobutyl-1-methyl-3,7dihydro-purine-2,6-dione,MH⁺ 467.

Method O

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.29 g, 1.9mmol) is added to5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.40 g, 1.9mmol)) and (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid (0.39g, 1.78 mmol) in methanol and water and the mixture is stirred atambient temperature for 2 hours. The methanol is evaporated and theresultant solid collected by filtration and recrystalised fromethylacetate/methanol. The resulting solid is heated under reflux withpiperidine for 8 h. The solution is filtered and the resulting solutionwashed with water and brine, dried over sodium sulphate, filtered andconcentrated. Further purification by flash silica column chromatography(eluant: ethylacetate/methanol) yields a solid which is dissolved 20% 1NNaOH/methanol and heated to reflux for 2 h. Concentration, addition ofwater and extraction with ethyl acetate gives an organic fraction whichis washed with water and brine, dried over Na2SO4, filtered andconcentrated to give8-(6,7-dimethoxy-1-piperidin-1-yl-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione,MH⁺ 507.

NMR Data for Examples (¹H 400 MHz DMSO-d6)

EXAMPLE 12

δ 325 (s 3H), 3.92 (s 3H), 4.02 (s 3H), 4.65 (s 2H), 7.70 (s 1H), 7.88(s 1H), 8.45 (s 1H), 9.42 (s 1H), 11.1 (s 1H), 13.60 (s 1H)

EXAMPLE 13

δ 3.20 (s 3H), 4.95 (s 3H), 4.00 (s 3H), 4.52 (d J 4 2H), 4.70 (s 2H),5.04 (d J 18 1H), 5.09 (d J 10 1H), 5.88 (m 1H), 7.60 (s 1H), 7.88 (s1H), 8.46 (s 1H), 9.42 (s 1H), 13.7 (s 1H).

EXAMPLE 14

δ 020-0.40 (m 4H), 1.10-1.30 (m 1H), 3.21 (s 3H), 3.81 (m 2H), 3.98 (s3H), 4.03 Is 3H), 4.66 (s 2H), 7.65 (s 1H), 7.85 (s 1H), 8.45 (s 1H),9.39 (s 1H), 13.70 (s 1H).

EXAMPLE 15

δ 0.82 (s 9H), 3.20 (s 3H), 3.78 (s 2H), 3.99 (s 3H), 4.04 (s 3H), 7.62(s 1H), 7.90 (s 1H), 8.45 (s 1H), 9.44 (s 1H), 13.60 (s 1H).

EXAMPLE 16

δ 0.81 (d J 7 12H), 1.98 (m 1H), 2.12 (m 1H), 3.70 (d J 8 2H), 3.78 (d J7 2H), 3.99 (s 3H), 4.05 (s 3H), 4.70 (s 2H), 7.65 (s 1H), 7.90 (s 1H),8.46 (s 1H), 9.45 (s 1H), 13.6 (s 1H).

EXAMPLE 17

δ 0.80-1.10 (m 6H), 1.40-1.60 (m 4H), 1.80 (m 1H), 3.15 (s 1H), 3.76 (d82H), 3.91 (s 3H), 4.02 (s 3H), 4.68 (s 2H), 7.60 (s 1H), 7.88 (s 1H),8.44 (s 1H), 13.60 (s 1H).

EXAMPLE 18

δ 1.69 (s 3H), 3.21 (s 3H), 3.98 (s 3H), 4.01 (s 3H), 4.46 (s 2H), 4.52(s 1H), 4.68 (s 2H), 4.76 (s 1H), 7.58 (s 1H), 7.84 (s 1H), 8.45 (s 1H),9.42 (s 1H), 13.60 (s 1H).

EXAMPLE 19

δ 1.50-1.85 (m 4H), 3.18 (s 3H), 3.S0-3.85 (m 4H), 3.95 (s 3H), 4.02 (s3H), 4.10-4.20 (m 1H), 4.70 (s 2H), 7.75 (s 1H), 7.920 (s 1H), 8.50 (s1H), 9.50 (s 1H), 13.60 (br s 1H).

EXAMPLE 20

δ 0.70-0.80 (m 6H), 0.99-1.10 (m 1H), 1.20-1.25 (m 1H), 1.88-2.00 (m 1H)3.21 is 3H), 3.64-3.80 (m 2H), 3.95 (s 3H), 4.00 (s 3H), 4.68 (s 2H),7.60 (s 1H), 7.80 (s 1H), 8.45 (s 1H), 9.42 (s 1H), 13.60 (br s 1H).

EXAMPLE 21

δ 0.83 (t J 8 3H), 1.63 (sextet J 8 2H), 3.83 (t J 8 2H), 3.99 (s 3H),4.05 (s 3H), 4.69 (s 2H), 7.64 (s 1H), 7.88 (s 1H), 8.44 (s 1H), 9.42 (s1H), 11.10 (s 1H), 13.60 (s 1H).

EXAMPLE 23

δ 0.80 (d J 7 6H), 3.18 (s 3H), 3.75 (d J 8 2H), 4.60 (s 2H), 6.32 (s2H), 7.71 (s 1H), 7.82 (s 1H), 8.50 (s 1H), 9.42 (s 1H), 13.50 (s 1H).

EXAMPLE 49

δ 0.12-0.25 (m 4H), 1.02-1.10 (m 1H),, 3.26 (s 3H), 3.68 (d J 7 2H),4.00 (s 3H), 4.80 (s 2H), 7.70 (d J 9 1H), 8.21 (d J 9 1H), 8.38 (s 1H),9.20 (s 1H), 13.10 is 1H).

EXAMPLE 863-Isobutyl-1-methyl-8-[1-(6-methyl-5-oxo-5,6-dihydro-[1,3]dioxolo[4,5-.g.]isoquinolin-8-yl)-ethyl]-3,7-dihydro-purine-2,6dione

Benzo[1,3]dioxol-5-ylmethyl-(2,2-dimethoxy-ethyl)-amine (Tetrahedron1968, 24, 1467) is treated with pyruvic acid according to the generalprocedure for Intermediate 22 to afford2-[1,3]dioxolo[4,5-.g.]isoquinolin-8-yl-propionic acid hydrochloride, mp224-226° C. Treatment with HCl gas in ethanol affords the correspondingethyl ester hydrochloride, mp 223-225° C. A solution of this compound(2.73 g, 10 mmol) in benzene (20 ml) is treated with dimethyl sulfate(1.26 g, 10 mmol), stirred at room temperature for 5 hours and thesolvent is evaporated. The crude oil is dissolved in water (20 ml),cooled to 0-5° C. and a solution of K₃Fe(CN)₆ (5.72 g, 17.4 mmol) inwater (25 ml) and sodium hydroxide (2.04 g, 51 mmol) in water (15 ml)are added. After 1.5 hours at 5° C., the reaction is adjusted to pH 2with concentrated hydrochloric acid and the product collected byfiltration then crystallised from methanol-dichloromethane to afford2-(6-methyl-5-oxo-5,6-dihydro-[1,3]dioxolo[4,5-.g.]isoquinolin-8-yl)-propionicacid, mp 290° C. (dec). This intermediate is then converted to thexanthine according to the general procedure of Method D, [MH]⁺ 452.

EXAMPLE 878-(6,7-Dimethoxy-quinolinyl-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione

Lithium diisopropylamide (2M pentane solution 2.46 ml, 4.92 mmol) andpotassium t-butoxide (0.552 g, 4.92 mmol) are added to THF (10 ml) at−70° C., followed by 6,7-dimethoxy-4-methyl-quinoline [J. Org. Chem.,1997, 623, 568] (1.0 g, 4.92 mmol). After 1 hour the reaction is pouredon to an excess of crushed dry ice and warmed to room temperatureovernight. Pyridine hydrochloride (0.57 g, 4.92 mmol) is added and thereaction partitioned between ether and water. The aqueous phase isevaporated, taken into hot methanol, treated with charcoal, filteredthrough celite and evaporated to afford(6,7-dimethoxy-quinolinyl-4-yl)-acetic acid, MH⁺ 248. This intermediateis then converted to the xanthine according to the general procedure ofMethod C, mp>250 ° C.

1-12. (canceled)
 13. A method of treating stable, unstable and variant(Prinzmetal) angina, hypertension, pulmonary hypertension, congestiveheart failure, atherosclerosis, conditions of reduced blood vesselpatency, or peripheral vascular disease comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of formula

in free or salt form, wherein R¹ is hydrogen or alkyl optionallysubstituted by hydroxy, alkoxy, or alkylthio, R² is hydrogen, alkyl,hydroxyalkyl, alkylcarbonyloxyalkyl, alkoxyalkyl, alkylthioalkyl,alkenyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl in which the arylring thereof is optionally fused to a 5-membered heterocyclic group oris optionally substituted by one or more substituents selected fromalkoxy, amino, alkylamino, dialkylamino, acylamino, halogen, hydroxy,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino or dialkylaminosulfonylamino, R³ is hydrogen or alkyloptionally substituted by hydroxy, alkoxy, or alkylthio, R⁴ is hydrogenor alkyl, R⁵ is a quinolinyl, isoquinolinyl or oxodihydroisoquinolinylgroup optionally fused to a 5-membered heterocyclic group and optionallysubstituted by one or more substituents selected from halogen, cyano,hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkoxy,alkylthio, alkenyl, alkoxycarbonyl, alkynyl, carboxyl, acyl, a group offormula —N(R⁶)R⁷, aryl optionally substituted by one or moresubstituents selected from halogen or alkoxy, or heteroaryl having 5 or6 ring atoms attached through a ring carbon atom to the indicated carbonatom, and R⁶ and R⁷ are each independently hydrogen or alkyl optionallysubstituted by hydroxy or alkoxy or one of R⁶ and R⁷ is hydrogen and theother is acyl, or R⁶ and R⁷ together with the nitrogen atom to whichthey are attached denote a 5- or 6-membered heterocyclyl group.
 14. Themethod of claim 13 wherein the PDE 5 inhibitor is3-isobutyl-8-(6-methoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione.
 15. The method of claim 13 wherein acondition of reduced blood vessel patency is post-percutaneoustransluminal coronary angioplasty.